Dr. Chong was recruited to Stanford from the Memorial Sloan Kettering (MSK) Cancer Center, where he led MSK's launch of the early drug development and immunotherapy clinical trials program in New Jersey. At MSK, Dr. Chong was a member of the gastrointestinal oncology service and was one of two MSK physicians in New Jersey who specialized in treating melanoma. Prior to joining MSK, Dr. Chong was a member of the thoracic oncology service at the Dana-Farber Cancer Institute and an attending physician at the Massachusetts General Hospital and Brigham and Women's Hospital, all ailiates of Harvard Medical School.
Dr. Chong completed his categorical residency in internal medicine at the Massachusetts General Hospital/Harvard Medical School, his oncology fellowship at the Dana-Farber Cancer Institute, and is board-certified in internal medicine and medical oncology. He has received research support from the American Society of Clinical Oncology (Young Investigator Award), Uniting Against Lung Cancer, and the American Cancer Society. Dr. Chong has been published in the New England Journal of Medicine, Nature, Nature Medicine, Nature Chemical Biology, JAMA Oncology, and his research on drug discovery has been featured in the New York Times and Popular Science.
Born and raised in Honolulu where he attended public schools, Dr. Chong sang in the Honolulu Boy Choir, and was the 1993 Honolulu Star Bulletin Newspaper Boy of the Year. He received his A.B. in biochemical sciences from Harvard University magna cum laude followed by an M.Phil. in Chemistry with Sir Alan Fersht at the University of Cambridge (Emmanuel College). He then received his MD and PhD in pharmacology from The Johns Hopkins University School of Medicine.
An intrepid traveler and avid long-distance runner, Dr. Chong has visited 54 countries and completed 126 marathons in all 50 states, 18 countries, and 6 on continents.
- Medical Oncology
Clinical Assistant Professor, Medicine - Oncology
Ambulatory CODE Team Leader, Dana-Farber Cancer Institute (2014 - 2015)
Assistant Attending Physician, Memorial Sloan-Kettering Cancer Center (2017 - Present)
Assistant in Medicine, Massachusetts General Hospital (2015 - 2017)
Assistant Professor, Weill Cornell Medical College (2017 - Present)
Attending Physician, Brigham and Women’s Hospital and Dana-Farber Cancer Institute (2015 - 2016)
Attending Physician, Kaiser Permanente, San Rafael, California (2016 - 2018)
Attending Physician, VA Boston (2017 - 2017)
Bone Marrow Harvest Team, Dana-Farber Cancer Institute (2013 - 2014)
Clinical Fellow in Medicine, Harvard Medical School (2008 - 2015)
Director of Phase I and Immunotherapy Clinical Trials Program, Memorial Sloan-Kettering Cancer Center, New Jersey (2017 - Present)
Hospitalist, Massachusetts General Hospital (2015 - 2017)
Inpatient Oncology Hospitalist, Women’s Cancer Center, Dana-Farber Cancer Institute/Brigham and Women’s Hospital (2014 - 2014)
Instructor in Medicine, Harvard Medical School (2015 - 2017)
Internal Medicine Intern, Massachusetts General Hospital (2008 - 2009)
Internal Medicine Resident, Massachusetts General Hospital (2009 - 2011)
Medical Oncology Fellow, Dana-Farber Cancer Institute (2011 - 2015)
Moonlighting Physician, Hospital Medicine Group, Massachusetts General Hospital (2010 - 2011)
Honors & Awards
Bial Award Diploma of Distinction, Bial Foundation for Medical Research and Portuguese Republic (2011)
Breast Cancer predoctoral fellowship, Office of the Congressionally Directed Medical Research Programs (2003-2006)
Fellow, American College of Physicians (2014)
Grand prize ($205,000), Rice University (2007)
Harold M. Weintraub Graduate Student Award, University of Washington (2006)
Honorable mention, Thomas Hoopes Prize, Harvard University (1998)
John Harvard Scholarship, Harvard University (1997-1998)
Michael Shano Young Investigator Award, The Johns Hopkins University School of Medicine (2007)
Rotary Foundation Ambassadorial Scholar, Rotary International (1998-1999)
Young Investigator Award, American Society for Clinical Oncology (2013)
Board Certification: American Board of Internal Medicine, Medical Oncology (2015)
Fellowship: Dana Farber Cancer Institute Hematology Oncology Fellowship (2015) MA
Board Certification: American Board of Internal Medicine, Internal Medicine (2011)
Residency: Massachusetts General Hospital Internal Medicine Residency (2011) MA
Medical Education: Johns Hopkins University School of Medicine (2008) MD
M.Phil., University of Cambridge, Chemistry (1999)
AB, Harvard University, Biochemical Sciences (1998)
- Bath JAMA ONCOLOGY 2017; 3 (10): 1308
Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer
CLINICAL CANCER RESEARCH
2017; 23 (1): 204–13
Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost and protracted timeline of drug discovery.In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes.This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1-transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nmol/L, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nmol/L, respectively), entrectinib (IC50 = 6/2,200/3,500 nmol/L), and PF-06463922 (IC50 = 1/270/2 nmol/L). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924 potently inhibited CD74-NTRK1-transformed compared with parental Ba/F3 cells (IC50 = 19 nmol/L vs. > 470 nmol/L). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response.While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib. Clin Cancer Res; 23(1); 204-13. ©2016 AACR.
View details for DOI 10.1158/1078-0432.CCR-15-1601
View details for Web of Science ID 000393876300024
View details for PubMedID 27370605
View details for PubMedCentralID PMC5203969
Characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone as a novel inhibitor of methionine aminopeptidases from Mycobacterium tuberculosis
CHURCHILL LIVINGSTONE. 2016: S73–S77
Mycobacterium tuberculosis (Mtb) and the Human Immunodeficiency Virus (HIV) pose a major public health threat. The 2015 World Health Organization (WHO) report estimates that one in three HIV deaths is due to Mtb, the causative agent of Tuberculosis (TB). The lethal synergy between these two pathogens leads to a decline in the immune function of infected individuals as well as a rise in morbidity and mortality rates. The deadly interaction between TB and HIV, along with the heightened emergence of drug resistance, drug-drug interactions, reduced drug efficacy and increased drug toxicity, has made the therapeutic management of co-infected individuals a major challenge. Hence, the development of new drug targets and/or new drug leads are imperative for the effective therapeutic management of co-infected patients. Here, we report the characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (311), a known inhibitor of HIV-1 replication and transcription as a new inhibitor of methionine aminopeptidases (MetAPs) from Mycobacterium tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. The essential role of MetAP in microbes makes it a promising chemotherapeutic target. We demonstrated that 311 is a potent and selective inhibitor of MtMetAP1a and MtMetAP1c. Furthermore, we found that 311 is active against replicating and aged non-growing Mtb at low micromolar concentrations. These results suggest that 311 is a promising lead for the development of novel class of therapeutic agents with dual inhibition of TB and HIV for the treatment of TB-HIV co-infection.
View details for DOI 10.1016/j.tube.2016.09.025
View details for Web of Science ID 000390365700011
View details for PubMedID 27856197
Anti-PD-1 Inhibitor-Related Pneumonitis in Non-Small Cell Lung Cancer
CANCER IMMUNOLOGY RESEARCH
2016; 4 (4): 289–93
The recent approval of two PD-1 inhibitors for the treatment of non-small cell lung cancer (NSCLC) has rapidly led to the widespread use of these agents in oncology practices. Pneumonitis has been recognized as a potentially life-threatening adverse event among NSCLC patients treated with PD-1 inhibitors; however, the detailed clinical and radiographic manifestations of this entity remain to be described. We report on two cases of anti-PD-1 pneumonitis in advanced NSCLC patients treated with nivolumab after its FDA approval. Both patients presented with ground-glass and reticular opacities and consolidations in a peripheral distribution on CT, demonstrating a radiographic pattern of cryptogenic organizing pneumonia. Consolidations were extensive and rapidly developed within 8 weeks of therapy in both cases. Both patients were treated with corticosteroids with subsequent improvement of respiratory symptoms and radiographic findings. One patient experienced recurrent pneumonitis after completing corticosteroid taper, or a "pneumonitis flare," in the absence of nivolumab retreatment, with subsequent improvement upon corticosteroid readministration. With the increasing use of immune checkpoint inhibitors in a growing number of tumor types, awareness of the radiographic and clinical manifestations of PD-1 inhibitor-related pneumonitis will be critical for the prompt diagnosis and management of this potentially serious adverse event.
View details for DOI 10.1158/2326-6066.CIR-15-0267
View details for Web of Science ID 000375410000003
View details for PubMedID 26865455
View details for PubMedCentralID PMC4818710
Targeted therapy for Epstein-Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation
2015; 6 (31): 31018–29
The constant presence of the viral genome in Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) suggests the applicability of novel EBV-targeted therapies. The antiviral nucleoside drug, ganciclovir (GCV), is effective only in the context of the viral lytic cycle in the presence of EBV-encoded thymidine kinase (TK)/protein kinase (PK) expression. In this study, screening of the Johns Hopkins Drug Library identified gemcitabine as a candidate for combination treatment with GCV. Pharmacological induction of EBV-TK or PK in EBVaGC-originated tumor cells were used to study combination treatment with GCV in vitro and in vivo. Gemcitabine was found to be a lytic inducer via activation of the ataxia telangiectasia-mutated (ATM)/p53 genotoxic stress pathway in EBVaGC. Using an EBVaGC mouse model and a [125I] fialuridine (FIAU)-based lytic activation imaging system, we evaluated gemcitabine-induced lytic activation in an in vivo system and confirmed the efficacy of gemcitabine-GCV combination treatment. This viral enzyme-targeted anti-tumor strategy may provide a new therapeutic approach for EBVaGCs.
View details for DOI 10.18632/oncotarget.5041
View details for Web of Science ID 000363185200058
View details for PubMedID 26427042
View details for PubMedCentralID PMC4741585
Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors
2014; 86 (2): 241–46
The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012.300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I-III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4-32), compared to 3 (1%) patients with typical carcinoid (range, 8-12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum-etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide+platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6-72 months).These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.
View details for DOI 10.1016/j.lungcan.2014.08.012
View details for Web of Science ID 000344438400023
View details for PubMedID 25218177
View details for PubMedCentralID PMC4293119
The quest to overcome resistance to EGFR-targeted therapies in cancer
2013; 19 (11): 1389–1400
All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.
View details for DOI 10.1038/nm.3388
View details for Web of Science ID 000326920300017
View details for PubMedID 24202392
View details for PubMedCentralID PMC4049336
Substituted oxines inhibit endothelial cell proliferation and angiogenesis
ORGANIC & BIOMOLECULAR CHEMISTRY
2012; 10 (15): 2979–92
Two substituted oxines, nitroxoline (5) and 5-chloroquinolin-8-yl phenylcarbamate (22), were identified as hits in a high-throughput screen aimed at finding new anti-angiogenic agents. In a previous study, we have elucidated the molecular mechanism of antiproliferative activity of nitroxoline in endothelial cells, which comprises of a dual inhibition of type 2 human methionine aminopeptidase (MetAP2) and sirtuin 1 (SIRT1). Structure-activity relationship study (SAR) of nitroxoline offered many surprises where minor modifications yielded oxine derivatives with increased potency against human umbilical vein endothelial cells (HUVEC), but with entirely different as yet unknown mechanisms. For example, 5-nitrosoquinolin-8-ol (33) inhibited HUVEC growth with sub-micromolar IC(50), but did not affect MetAP2 or MetAP1, and it only showed weak inhibition against SIRT1. Other sub-micromolar inhibitors were derivatives of 5-aminoquinolin-8-ol (34) and 8-sulfonamidoquinoline (32). A sulfamate derivative of nitroxoline (48) was found to be more potent than nitroxoline with the retention of activities against MetAP2 and SIRT1. The bioactivity of the second hit, micromolar HUVEC and MetAP2 inhibitor carbamate 22 was improved further with an SAR study culminating in carbamate 24 which is a nanomolar inhibitor of HUVEC and MetAP2.
View details for DOI 10.1039/c2ob06978d
View details for Web of Science ID 000301958100013
View details for PubMedID 22391578
View details for PubMedCentralID PMC3767132
Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis
2011; 91: S61–S65
Mycobacterium tuberculosis, the causative agent of tuberculosis claims about five thousand lives daily world-wide, while one-third of the world is infected with dormant tuberculosis. The increased emergence of multi- and extensively drug-resistant strains of M. tuberculosis (Mtb) has heightened the need for novel antimycobacterial agents. Here, we report the discovery of 7-bromo-5-chloroquinolin-8-ol (CLBQ14)-a congener of clioquinol (CQ) as a potent and selective inhibitor of two methionine aminopeptidases (MetAP) from M. tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. N-terminal methionine excision (NME) is a universally conserved process required for the post-translational modification of a significant part of the proteome. The essential role of MetAP in microbes makes it a promising target for the development of new therapeutics. Using a target-based approach in a high-throughput screen, we identified CLBQ14 as a novel MtMetAP inhibitor with higher specificity for both MtMetAP1s relative to their human counterparts. We also found that CLBQ14 is potent against replicating and aged non-growing Mtb at low micro molar concentrations. Furthermore, we observed that the antimycobacterial activity of this pharmacophore correlates well with in vitro enzymatic inhibitory activity. Together, these results revealed a new mode of action of clioquinol and its congeners and validated the therapeutic potential of this pharmacophore for TB chemotherapy.
View details for DOI 10.1016/j.tube.2011.10.012
View details for Web of Science ID 000298637400012
View details for PubMedID 22115541
A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment
2011; 1 (1): 68–77
Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically-used drugs might have utility for treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large, prospective cohort study. In stage 1, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate given its potency in inhibiting proliferation in vitro (mean IC₅₀=163 nM) and common use. In stage 2, we evaluated the association between the leading candidate drug from stage 1 and prostate cancer risk in 47,884 men followed 1986-2006. Regular digoxin users (versus nonusers: RR=0.76, 95% CI 0.61-0.95), especially users for ≥ 10 years (RR=0.54, 95% CI 0.37-0.79, P-trend<0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro and its use was associated with a 25% lower prostate cancer risk.Our two-stage transdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing.
View details for DOI 10.1158/2159-8274.CD-10-0020
View details for Web of Science ID 000295780300023
View details for PubMedID 22140654
View details for PubMedCentralID PMC3227223
Effect of Nitroxoline on Angiogenesis and Growth of Human Bladder Cancer
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
2010; 102 (24): 1855–73
Angiogenesis plays an important role in tumor growth and metastasis; therefore, inhibition of angiogenesis is a promising strategy for developing new anticancer drugs. Type 2 methionine aminopeptidase (MetAP2) protein is likely a molecular target of angiogenesis inhibitors.Nitroxoline, an antibiotic used to treat urinary tract infections, was identified from a high-throughput screen of a library of 175,000 compounds for MetAP2 inhibitors and from a parallel screen using the Johns Hopkins Drug Library to identify currently used clinical drugs that can also inhibit human umbilical vein endothelial cells (HUVEC) proliferation. To investigate the mechanism of action of nitroxoline, inhibition of MetAP2 activity and induction of senescence were assessed in HUVEC. To test the antiangiogenic activity of nitroxoline, endothelial tube formation in Matrigel and microvessel formation in Matrigel plugs in vivo were assessed. Antitumor efficacy of nitroxoline was evaluated in mouse models of human breast cancer xenograft (n = 10) and bladder cancer orthotopic xenograft (n = 11). Furthermore, the mechanism of action of nitroxoline was investigated in vivo.Nitroxoline inhibited MetAP2 activity in vitro (half maximal inhibitory concentration [IC(50)] = 54.8 nM, 95% confidence interval [CI] = 22.6 to 132.8 nM) and HUVEC proliferation (IC(50) = 1.9 μM, 95% CI = 1.54 to 2.39 μM). Nitroxoline inhibited MetAP2 activity in HUVEC in a dose-dependent manner and induced premature senescence in a biphasic manner. Nitroxoline inhibited endothelial tube formation in Matrigel and reduced microvessel density in vivo. Mice (five per group) treated with nitroxoline showed a 60% reduction in tumor volume in breast cancer xenografts (tumor volume on day 30, vehicle vs nitroxoline, mean = 215.4 vs 86.5 mm(3), difference = 128.9 mm(3), 95% CI = 32.9 to 225.0 mm(3), P = .012) and statistically significantly inhibited growth of bladder cancer in an orthotopic mouse model (tumor bioluminescence intensities of vehicle [n = 5] vs nitroxoline [n = 6], P = .045).Nitroxoline shows promise as a potential therapeutic antiangiogenic agent.
View details for DOI 10.1093/jnci/djq457
View details for Web of Science ID 000285419800011
View details for PubMedID 21088277
View details for PubMedCentralID PMC3001967
- An Unnecessary Death in Zambia AMERICAN JOURNAL OF MEDICINE 2010; 123 (7): 669
Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth
2010; 17 (4): 388-399
In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.
View details for DOI 10.1016/j.ccr.2010.02.027
View details for PubMedID 20385363
Itraconazole as a novel Hedgehog pathway antagonist in cancer therapy
AMER ASSOC CANCER RESEARCH. 2009
View details for Web of Science ID 000209702604342
- Mysterious Metformin ONCOLOGIST 2009; 14 (12): 1178–81
Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes
2008; 3 (12): e4009
The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders.
View details for DOI 10.1371/journal.pone.0004009
View details for Web of Science ID 000265462400010
View details for PubMedID 19104661
View details for PubMedCentralID PMC2602975
Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
2008; 52 (9): 3106–12
No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 microM paromomycin or 27 microM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.
View details for DOI 10.1128/AAC.00207-08
View details for Web of Science ID 000258667300017
View details for PubMedID 18591280
View details for PubMedCentralID PMC2533469
Idiopathic Infantile Arterial Calcification: The Spectrum of Clinical Presentations
PEDIATRIC AND DEVELOPMENTAL PATHOLOGY
2008; 11 (5): 405–15
Idiopathic infantile arterial calcification (IIAC) is a rare disorder characterized by extensive calcification of medium and large arteries. We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. At autopsy the infant was found to have cardiomegaly, myocardial infarctions and multifocal calcifications of the aorta and arteries in the lungs, heart, thyroid, spleen, and testis. Calcification extended from the internal elastic lamina into the intima and media and was associated with a giant-cell reaction and smooth muscle proliferation. A search of the English language medical literature identified 161 IIAC case reports. Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory distress in a previously healthy infant. Significantly, 19 of 22 IIAC survivors presented at less than 2 weeks of age, and 15 survivors were treated with diphosphonates.
View details for DOI 10.2350/07-06-0297.1
View details for Web of Science ID 000260969600012
View details for PubMedID 17990935
Pyrrolidine dithiocarbamate and diethyldithiocarbamate are active against growing and nongrowing persister Mycobacterium tuberculosis
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
2007; 51 (12): 4495–97
Diethyldithiocarbamate (DETC) and pyrrolidine dithiocarbamate (PDTC) were highly active against tubercle bacilli, with MICs of 8 microg/ml and 0.13 microg/ml, respectively. DETC and PDTC were active against old cultures, enhanced pyrazinamide or pyrazinamide/rifampin activity, and had serum inhibitory titers of 1:2 and 1:4, respectively, in mice given 100 mg/kg orally.
View details for DOI 10.1128/AAC.00753-07
View details for Web of Science ID 000251472100046
View details for PubMedID 17876006
View details for PubMedCentralID PMC2168016
Catalysis of zinc transfer by D-penicillamine to secondary chelators
JOURNAL OF MEDICINAL CHEMISTRY
2007; 50 (22): 5524–27
The antiarthritis drug D-penicillamine (D-PEN) catalyzes zinc(II) transfer from carboxypeptidase A to chelators such as thionein and EDTA at a rate constant up to 400-fold faster than the uncatalyzed release. Once D-PEN releases zinc(II) from enzyme stronger chelators can tightly bind zinc(II) leading to complete and essentially irreversible inhibition. D-PEN is the first drug to inhibit a zinc protease by catalyzing metal removal, and the name "catalytic chelation" is proposed for this mechanism.
View details for DOI 10.1021/jm070803y
View details for Web of Science ID 000250557100031
View details for PubMedID 17918925
- New uses for old drugs NATURE 2007; 448 (7154): 645–46
Brief report - The HBV drug entecavir - Effects on HIV-1 replication and resistance
NEW ENGLAND JOURNAL OF MEDICINE
2007; 356 (25): 2614–21
Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.
View details for DOI 10.1056/NEJMoa067710
View details for Web of Science ID 000247351200008
View details for PubMedID 17582071
View details for PubMedCentralID PMC3069686
Inhibition of angiogenesis by the antifungal drug itraconazole
ACS CHEMICAL BIOLOGY
2007; 2 (4): 263–70
Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for inhibitors of human endothelial cell proliferation. One of the most promising and unexpected hits was itraconazole, a known antifungal drug. Itraconazole inhibits endothelial cell cycle progression at the G1 phase in vitro and blocks vascular endothelial growth factor/basic fibroblast growth factor-dependent angiogenesis in vivo. In attempts to delineate the mechanism of action of itraconazole, we found that human lanosterol 14alpha-demethylase (14DM) is essential for endothelial cell proliferation and may partially mediate the inhibition of endothelial cells by itraconazole. Together, these findings suggest that itraconazole has the potential to serve as an antiangiogenic drug and that lanosterol 14DM is a promising new target for discovering new angiogenesis inhibitors.
View details for DOI 10.1021/cb600362d
View details for Web of Science ID 000245946200022
View details for PubMedID 17432820
Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (39): 14548–53
With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets. The Plasmodium falciparum methionine aminopeptidase 1b (PfMetAP1b), one of four MetAP proteins encoded in the P. falciparum genome, was cloned, overexpressed, purified, and used to screen a 175,000-compound library for inhibitors. A family of structurally related inhibitors containing a 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activity studies led to the identification of a potent PfMetAP1b inhibitor, XC11, with an IC(50) of 112 nM. XC11 was highly selective for PfMetAP1b and did not exhibit significant cytotoxicity against primary human fibroblasts. Most importantly, XC11 inhibited the proliferation of P. falciparum strains 3D7 [chloroquine (CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and is active in mouse malaria models for both CQ-sensitive and CQ-resistant strains. These results suggest that PfMetAP1b is a promising target and XC11 is an important lead compound for the development of novel antimalarial drugs.
View details for DOI 10.1073/pnas.0604101103
View details for Web of Science ID 000240968100053
View details for PubMedID 16983082
View details for PubMedCentralID PMC1599997
Fumarranol, a rearranged fumagillin analogue that inhibits angiogenesis in vivo
JOURNAL OF MEDICINAL CHEMISTRY
2006; 49 (19): 5645–48
The fumagillin family of natural products inhibits angiogenesis through the irreversible inhibition of the type 2 methionine aminopeptidase (MetAP2). Herein is reported a novel fumagillin analogue named fumarranol. It is shown that, like fumagillin, fumarranol selectively inhibits MetAP2 and endothelial cell proliferation. It is also active in a mouse model of angiogenesis in vivo. Unlike TNP-470, fumarranol does not covalently bind to MetAP2. Fumarranol may serve as a lead for a new class of angiogenesis inhibitors.
View details for DOI 10.1021/jm060559v
View details for Web of Science ID 000240495600001
View details for PubMedID 16970390
A clinical drug library screen identifies astemizole as an antimalarial agent
NATURE CHEMICAL BIOLOGY
2006; 2 (8): 415–16
The high cost and protracted time line of new drug discovery are major roadblocks to creating therapies for neglected diseases. To accelerate drug discovery we created a library of 2,687 existing drugs and screened for inhibitors of the human malaria parasite Plasmodium falciparum. The antihistamine astemizole and its principal human metabolite are promising new inhibitors of chloroquine-sensitive and multidrug-resistant parasites, and they show efficacy in two mouse models of malaria.
View details for DOI 10.1038/nchembio806
View details for Web of Science ID 000239146800009
View details for PubMedID 16816845
Reading dynamic kinase activity in living cells for high-throughput screening
ACS CHEMICAL BIOLOGY
2006; 1 (6): 371–76
Protein kinases, as crucial signaling molecules, represent an emerging class of drug targets, and the ability to assay their activities in living cells with high-throughput screening should provide exciting opportunities for drug discovery and chemical and functional genomics. Here, we describe a general method for high-throughput reading of dynamic kinase activities using ratiometric fluorescent sensors, and showcase an example of reading intracellular activities of protein kinase A (PKA) and the cyclic adenosine monophosphate (cAMP)/PKA pathway downstream of many G-protein coupled receptors (GPCRs). We further demonstrate the first compound screen based on the ability of compounds to modulate dynamic kinase activities in living cells and show that such screening of a collection of clinical compounds has successfully identified modulators of the GPCR/cAMP/PKA pathway.
View details for DOI 10.1021/cb600202f
View details for Web of Science ID 000243869600016
View details for PubMedID 17163774
Identification of inosine monophosphate dehydrogenase as an anti-angiogenic drug target
FEDERATION AMER SOC EXP BIOL. 2005: A276
View details for Web of Science ID 000227610701651
Copper pathways in Plasmodium faliciparum infected erythrocytes indicate an efflux role for the copper P-ATPase
2004; 381: 803–11
Copper, like iron, is a transition metal that can generate oxygen radicals by the Fenton reaction. The Plasmodium parasite invades an erythrocyte host cell containing 20 microM copper, of which 70% is contained in the Cu/Zn SOD (cuprozinc superoxide dismutase). In the present study, we follow the copper pathways in the Plasmodium-infected erythrocyte. Metal-determination analysis shows that the total copper content of Percoll-purified trophozoite-stage-infected erythrocytes is 66% that of uninfected erythrocytes. This decrease parallels the decrease seen in Cu/Zn SOD levels in parasite-infected erythrocytes. Neocuproine, an intracellular copper chelator, arrests parasites at the ring-to-trophozoite stage transition and also specifically decreases intraparasitic levels of Cu/Zn SOD and catalase. Up to 150 microM BCS (2,9-dimethyl-4,7-diphenyl-1,10-phenanthrolinedisulphonic acid), an extracellular copper chelator, has no effect on parasite growth. We characterized a single copy PfCuP-ATPase (Plasmodium falciparum copper P-ATPase) transporter, which, like the Crypto-sporidium parvum copper P-ATPase, has a single copper-binding domain: 'Met-Xaa-Cys-Xaa-Xaa-Cys'. Recombinant expression of the N-terminal metal-binding domain reveals that the protein specifically binds reduced copper. Transcription of the PfCuP-ATPase gene is the highest at late ring stage/early trophozoite, and is down-regulated in the presence of neocuproine. Immunofluorescence and electron microscopy indicate the transporter to be both in the parasite and on the erythrocyte membrane. Both the decrease in total copper and the location of the PfCuP-ATPase gene indicate a copper-efflux pathway from the infected erythrocyte.
View details for DOI 10.1042/BJ20040335
View details for Web of Science ID 000223440600027
View details for PubMedID 15125686
View details for PubMedCentralID PMC1133890
Inhibition of heme crystal growth by antimalarials and other compounds: implications for drug discovery
2003; 66 (11): 2201–12
During intraerythrocytic infection, Plasmodium falciparum parasites crystallize toxic heme released during hemoglobin catabolism. The proposed mechanism of quinoline inhibition of crystal growth is either by a surface binding or a substrate sequestration mechanism. The kinetics of heme crystal growth was examined in this work using a new high-throughput crystal growth determination assay based on the differential solubility of free vs. crystalline FP in basic solutions. Chloroquine (IC(50)=4.3 microM) and quinidine (IC(50)=1.5 microM) showed a previously not recognized reversible inhibition of FP crystal growth. This inhibition decreased by increasing amounts of heme crystal seed, but not by greater amounts of FP substrate. Crystal growth decreases as pH rises from 4.0 to 6.0, except for a partial local maxima reversal from pH 5.0 to 5.5 that coincides with increased FP solubility. The new crystal growth determination assay enabled a partial screen of existing clinical drugs. Nitrogen heterocycle cytochrome P450 inhibitors also reversibly blocked FP crystal growth, including the azole antifungal drugs clotrimazole (IC(50)=12.9 microM), econazole (IC(50)=19.7 microM), ketoconazole (IC(50)=6.5 microM), and miconazole (IC(50)=21.4 microM). Fluconazole did not inhibit. Both subcellular fractionation of parasites treated with subinhibitory concentrations of ketoconazole and in vitro hemozoin growth assays demonstrated copurification of hemozoin and ketoconazole. The chemical diversity of existing CYP inhibitor libraries that bind FP presents new opportunities for the discovery of antimalarial drugs that block FP crystal growth by a surface binding mechanism and possibly interfere with other FP-sensitive Plasmodium pathways.
View details for DOI 10.1016/j.bcp.2003.08.009
View details for Web of Science ID 000186847300015
View details for PubMedID 14609745
Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 angstrom - Inhibitor-induced conformational changes
2000; 39 (33): 10082–89
D-Cysteine differs from the antiarthritis drug D-penicillamine by only two methyl groups on the beta-carbon yet inhibits carboxypeptidase A (CPD) by a distinct mechanism: D-cysteine binds tightly to the active site zinc, while D-penicillamine catalyzes metal removal. To investigate the structural basis for this difference, we solved the crystal structure of carboxypeptidase A complexed with D-cysteine (D-Cys) at 1.75-A resolution. D-Cys binds the active site zinc with a sulfur ligand and forms additional interactions with surrounding side chains of the enzyme. The structure explains the difference in potency between D-Cys and L-Cys and provides insight into the mechanism of D-penicillamine inhibition. D-Cys binding induces a concerted motion of the side chains around the zinc ion, similar to that found in other carboxypeptidase-inhibitor crystal structures and along a limited path. Analysis of concerted motions of CPD and CPD-inhibitor crystal structures reveals a clustering of these structures into distinct groups. Using the restricted conformational flexibility of a drug target in this type of analysis could greatly enhance efficiency in drug design.
View details for DOI 10.1021/bi000952h
View details for Web of Science ID 000088945800008
View details for PubMedID 10955996
Inhibition of carboxypeptidase A by D-penicillamine: Mechanism and implications for drug design
2000; 39 (25): 7580–88
Zinc metalloprotease inhibitors are usually designed to inactivate the enzyme by forming a stable ternary complex with the enzyme and active-site zinc. D-Cysteine inhibits carboxypeptidase, ZnCPD, by forming such a complex, with a K(i) of 2.3 microM. In contrast, the antiarthritis drug D-penicillamine, D-PEN, which differs from D-Cys only by the presence of two methyl groups on the beta-carbon, inhibits ZnCPD by promoting the release of the active-site zinc. We have given the name catalytic chelator to such inhibitors. Inhibition is a two-step process characterized by formation of a complex with the enzyme (K(i(initial)) = 1.2 mM) followed by release of the active-site zinc at rates up to 420-fold faster than the spontaneous release. The initial rate of substrate hydrolysis at completion of the second step also depends on D-PEN concentration, reflecting formation of a thermodynamic equilibrium governed by the stability constants of chelator and apocarboxypeptidase for zinc (K(i(final)) = 0.25 mM). The interaction of D-PEN and D-Cys with the active-site metal has been examined by replacing the active-site zinc by a chromophoric cobalt atom. Both inhibitors perturb the d-d transitions of CoCPD in the 500-600 nm region within milliseconds of mixing but only the CoCPD.D-Cys complex displays a strong S --> Co(II) charge-transfer band at 340 nm indicative of a metal-sulfur bond. While the D-Cys complex is stable, the CoCPD.D-PEN complex breaks down to apoenzyme and Co(D-PEN)(2) with a half-life of 0.5 s. D-PEN is the first drug found to inhibit a metalloprotease by increasing the dissociation rate constant of the active-site metal. The ability of D-PEN to catalyze metal removal from carboxypeptidase A and other zinc proteases suggests a possible mechanism of action in arthritis and Wilson's disease and may also underlie complications associated with its clinical use.
View details for DOI 10.1021/bi000101+
View details for Web of Science ID 000087918200030
View details for PubMedID 10858308
Hyperglycemia in hummingbirds and its consequences for hemoglobin glycation
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY
1998; 120 (3): 409–16
We measured levels of glucose and glycated hemoglobin in the blood of three of the world's smallest nectarivorous birds, the Anna's (Calypte anna), Costa's (Calypte costae), and ruby-throated hummingbirds (Archilochus colubris). Plasma glucose levels of hummingbirds that were fasted overnight (17 mM) were higher than those in any mammal and are among the highest ever measured in a fasting vertebrate. Glucose levels in hummingbirds just after feeding were extreme, rising as high as 42 mM. The surprisingly high blood glucose concentrations in hummingbirds were accompanied by glycated hemoglobin levels that are the highest ever measured in birds but are lower than those of non-diabetic humans. How hummingbirds tolerate blood glucose levels that cause serious neurological and microvascular pathologies in diabetic humans and animals remains unknown.
View details for DOI 10.1016/S1095-6433(98)10039-9
View details for Web of Science ID 000075819600004
View details for PubMedID 9787825