Chenzhou Hao

All Publications

• An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations. Science translational medicine Westberg, M., Su, Y., Zou, X., Huang, P., Rustagi, A., Garhyan, J., Patel, P. B., Fernandez, D., Wu, Y., Hao, C., Lo, C. W., Karim, M., Ning, L., Beck, A., Saenkham-Huntsinger, P., Tat, V., Drelich, A., Peng, B. H., Einav, S., Tseng, C. K., Blish, C., Lin, M. Z. 2024; 16 (738): eadi0979

  Abstract

  Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

  View details for DOI 10.1126/scitranslmed.adi0979

  View details for PubMedID 38478629

• Development of a cell-permeable adenine-derived probe for capture of nucleotide-binding proteins in living cells CHINESE CHEMICAL LETTERS Liu, L., Chen, R., Xue, G., Hao, C., Weng, W., Pan, Z. 2024; 35 (3)

  View details for DOI 10.1016/j.cclet.2023.108455

  View details for Web of Science ID 001137958500001

• Optically activated MEK1/2 inhibitors (Opti-MEKi) as potential antimelanoma agents EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Hao, C., Li, X., Wang, Z., Liu, L., He, F., Pan, Z. 2023; 251: 115236

  Abstract

  Mitogen-activated protein kinase kinases 1/2 (MEK1/2) play critical roles in the canonical RAS/RAF/MEK/ERK pathway. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed, and three of them were clinically approved for the treatment of BRAFV600 -mutant melanoma. However, the accompanying side effects of the systemically administered MEK1/2 drugs largely constrain their tolerable doses and efficacy. In this study, a series of mirdametinib-based optically activatable MEK1/2 inhibitors (opti-MEKi) were designed and synthesized. A structural-based design led to the discovery of photocaged compounds with dramatically diminished efficacy in vitro, whose activities can be spatiotemporally induced by short durations of irradiation of ultraviolet (365 nm) light. We demonstrated the robust photoactivation of MEK1/2 inhibition and antimelanoma activity in cultured human cells, as well as in a xenograft zebrafish model. Taken together, the modular approach presented herein provides a method for the optical control of MEK1/2 inhibitor activity, and these data support the further development of optically activatable agents for light-mediated antimelanoma phototherapy.

  View details for DOI 10.1016/j.ejmech.2023.115236

  View details for Web of Science ID 000952448600001

  View details for PubMedID 36924668

• Design, synthesis, biological evaluation and molecular docking study of novel thieno[3,2-<i>d</i>]pyrimidine derivatives as potent FAK inhibitors EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Wang, R., Yu, S., Zhao, X., Chen, Y., Yang, B., Wu, T., Hao, C., Zhao, D., Cheng, M. 2020; 188: 112024

  Abstract

  A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC50 = 28.2 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.16, 0.27, and 0.19 μM, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC50 = 3.32 μM) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery.

  View details for DOI 10.1016/j.ejmech.2019.112024

  View details for Web of Science ID 000515428100033

  View details for PubMedID 31923858

• Synthesis, bioconversion, pharmacokinetic and pharmacodynamic evaluation of <i>N</i>-isopropyl-oxy-carbonyloxymethyl prodrugs of CZh-226, a potent and selective PAK4 inhibitor EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Guo, J., Wang, T., Wu, T., Zhang, K., Yin, W., Zhu, M., Pang, Y., Hao, C., He, Z., Cheng, M., Liu, Y., Zheng, J., Gu, J., Zhao, D. 2020; 186: 111878

  Abstract

  We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.

  View details for DOI 10.1016/j.ejmech.2019.111878

  View details for Web of Science ID 000509616800025

  View details for PubMedID 31757524

• Design, synthesis, biological evaluation and molecular modeling of novel 1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridine derivatives as potential anti-tumor agents BIOORGANIC CHEMISTRY Wang, R., Chen, Y., Yang, B., Yu, S., Zhao, X., Zhang, C., Hao, C., Zhao, D., Cheng, M. 2020; 94: 103474

  Abstract

  A class of 3-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were designed, synthesized and evaluated for their in vitro biological activities against maternal embryonic leucine zipper kinase (MELK). Among these derivatives, the optimized compound 16h exhibited potent enzyme inhibition (IC50 = 32 nM) and excellent anti-proliferative effect with IC50 values from 0.109 μM to 0.245 μM on A549, MDA-MB-231 and MCF-7 cell lines. The results of flow cytometry indicated that 16h promoted apoptosis of A549 cells in a dose-dependent manner and effectively arrested A549 cells in the G0/G1 phase. Further investigation indicated that compound 16h potently suppressed the migration of A549 cells, had moderate stability in rat liver microsomes and showed moderate inhibitory activity against various subtypes of human cytochrome P450. However, compound 16h is a multi-target kinase inhibitor and recently several studies reported MELK expression is not required for cancer growth, suggesting that compound 16h suppressed the proliferation and migration of cancer cells should through an off-target mechanism. Collectively, compound 16h has the potential to serve as a new lead compound for further anticancer drug discovery.

  View details for DOI 10.1016/j.bioorg.2019.103474

  View details for Web of Science ID 000505596300120

  View details for PubMedID 31859010

• Design, synthesis and biological evaluation of novel 7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidine derivatives as potential FAK inhibitors and anticancer agents EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Wang, R., Chen, Y., Zhao, X., Yu, S., Yang, B., Wu, T., Guo, J., Hao, C., Zhao, D., Cheng, M. 2019; 183: 111716

  Abstract

  A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC50 values in the 10-8-10-9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC50 = 3.2 μM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors.

  View details for DOI 10.1016/j.ejmech.2019.111716

  View details for Web of Science ID 000498308700043

  View details for PubMedID 31550660

• Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Guo, J., Zhao, F., Yin, W., Zhu, M., Hao, C., Pang, Y., Wu, T., Wang, J., Zhao, D., Li, H., Cheng, M. 2018; 155: 197-209

  View details for DOI 10.1016/j.ejmech.2018.05.051

  View details for Web of Science ID 000441856300016

  View details for PubMedID 29886323

• Discovery of 2-(4-Substituted-piperidin/piperazine-1-yl)-<i>N</i>-(5-cyclopropyl-1<i>H</i>-pyrazol-3-yl)-quinazoline-2,4-diamines as PAK4 Inhibitors with Potent A549 Cell Proliferation, Migration, and Invasion Inhibition Activity MOLECULES Wu, T., Pang, Y., Guo, J., Yin, W., Zhu, M., Hao, C., Wang, K., Wang, J., Zhao, D., Cheng, M. 2018; 23 (2)

  Abstract

  A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 μM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 μM and 0.068 μM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.

  View details for DOI 10.3390/molecules23020417

  View details for Web of Science ID 000426436300197

  View details for PubMedID 29443911

  View details for PubMedCentralID PMC6100240

• Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors JOURNAL OF MEDICINAL CHEMISTRY Hao, C., Zhao, F., Song, H., Guo, J., Li, X., Jiang, X., Huan, R., Song, S., Zhang, Q., Wang, R., Wang, K., Pang, Y., Liu, T., Lu, T., Huang, W., Wang, J., Lin, B., He, Z., Li, H., Li, F., Zhao, D., Cheng, M. 2018; 61 (1): 265-285

  Abstract

  Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.

  View details for DOI 10.1021/acs.jmedchem.7b01342

  View details for Web of Science ID 000422810800015

  View details for PubMedID 29190083

• The therapeutic potential of CETP inhibitors: a patent review EXPERT OPINION ON THERAPEUTIC PATENTS Wang, X., Li, W., Hao, L., Xie, H., Hao, C., Liu, C., Li, W., Xiong, X., Zhao, D. 2018; 28 (4): 331-340

  Abstract

  Epidemiological studies have identified that high levels of low-density lipoprotein-cholesterol (LDL-C) and low levels of high-density lipoprotein-cholesterol (HDL-C) are two independent causes of cardiovascular disease (CVD). Statins, niacin and fibrate are used for the treatment of CVD. However, some defects are shown in the treatment process. Thus, there is a demand for better treatment strategies that confer preferable efficacy with fewer side effects. Cholesteryl ester transfer protein (CETP) promotes the movement of CEs from HDL to LDL and VLDL in exchange for triglycerides (TGs).In this review, we reviewed the development and therapeutic applications of CETP inhibitors. A comprehensive review of the patents and pharmaceutical applications between 2009 and 2017 has been highlighted.Recently, CETP inhibitors have attracted considerable interest in atherosclerosis-related disease. There are four drugs (torcetrapib, anacetrapib, evacetrapib and dalcetrapib) that have been clinically evaluated in phase III clinical trials and showed promising results in raising HDL-C levels, but there were suboptimal performances in reducing the risk of cardiovascular events with all the compounds. The correlation between plasma HDL-C levels and CVD incidence needs further verification. The timeline is still long for CETP inhibitors to emerge from the treatment of CVD.

  View details for DOI 10.1080/13543776.2018.1439476

  View details for Web of Science ID 000427055500005

  View details for PubMedID 29424255

• Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Zhao, S., Zhang, X., Wei, P., Su, X., Zhao, L., Wu, M., Hao, C., Liu, C., Zhao, D., Cheng, M. 2017; 137: 96-107

  View details for DOI 10.1016/j.ejmech.2017.05.043

  View details for Web of Science ID 000407412200008

• Discovery of indolin-2-one derivatives as potent PAK4 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study BIOORGANIC & MEDICINAL CHEMISTRY Guo, J., Zhu, M., Wu, T., Hao, C., Wang, K., Yan, Z., Huang, W., Wang, J., Zhao, D., Cheng, M. 2017; 25 (13): 3500-3511

  Abstract

  Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50=22nM, 16nM and 27nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50=0.83μM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions.

  View details for DOI 10.1016/j.bmc.2017.04.047

  View details for Web of Science ID 000402941700021

  View details for PubMedID 28502459

• Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Hao, C., Huang, W., Li, X., Guo, J., Chen, M., Yan, Z., Wang, K., Jiang, X., Song, S., Wang, J., Zhao, D., Li, F., Cheng, M. 2017; 131: 1-13

  Abstract

  Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 μM) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 μM). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4.

  View details for DOI 10.1016/j.ejmech.2017.02.063

  View details for Web of Science ID 000399266500001

  View details for PubMedID 28284095

• Synthesis of novel β-propanamides to inhibit cholesteryl ester transfer protein (CETP) CHINESE CHEMICAL LETTERS Xie, H., Liu, C., Li, Y., Bai, C., Hao, C., Guo, J., Luo, C., Zhao, D., Cheng, M. 2017; 28 (2): 260-263

  View details for DOI 10.1016/j.cclet.2016.10.016

  View details for Web of Science ID 000393929300018

• Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies BIOORGANIC & MEDICINAL CHEMISTRY Zhao, D., Zhao, S., Zhao, L., Zhang, X., Wei, P., Liu, C., Hao, C., Sun, B., Su, X., Cheng, M. 2017; 25 (2): 750-758

  Abstract

  Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125-2μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization.

  View details for DOI 10.1016/j.bmc.2016.11.051

  View details for Web of Science ID 000392906500031

  View details for PubMedID 27955926

• Design, synthesis, and structure-activity relationship studies of benzothiazole derivatives as antifungal agents EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Zhao, S., Zhao, L., Zhang, X., Liu, C., Hao, C., Xie, H., Sun, B., Zhao, D., Cheng, M. 2016; 123: 514-522

  Abstract

  A series of compounds with benzothiazole and amide-imidazole scaffolds were designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. The antifungal activity of these compounds was evaluated in vitro, and their structure-activity relationships (SARs) were evaluated. The synthesized compounds showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans. The most potent compounds 14o, 14p, and 14r exhibited potent activity, with minimum inhibitory concentration (MIC) values in the range of 0.125-2 μg/mL. Preliminary mechanism studies revealed that the compound 14p might act by inhibiting the CYP51 of Candida albicans. The SARs and binding mode established in this study are useful for further lead optimization.

  View details for DOI 10.1016/j.ejmech.2016.07.067

  View details for Web of Science ID 000385319000041

  View details for PubMedID 27494168

• Design, synthesis and biological evaluation of novel cholesteryl ester transfer protein inhibitors bearing a cycloalkene scaffold EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Liu, C., Luo, C., Hao, L., Wu, Q., Xie, H., Zhao, S., Hao, C., Zhao, D., Cheng, M. 2016; 123: 419-430

  Abstract

  Cholesteryl ester transfer protein (CETP) is a potential target for cardiovascular disease therapy as inhibition of CETP leads to increased HDL-C in humans. Based on the structure of Merck's biphenyl CETP inhibitor, we designed novel N,N-substituted-cycloalkenyl-methylamine scaffold derivatives by utilizing core replacement and conformational restriction strategies. Consequently, twenty-eight compounds were synthesized and evaluated for their inhibitory activity against CETP. Their preliminary structure-activity relationships (SARs) studies indicate that polar substituents were tolerated in moiety A and hydrophobic alkyl groups at the 5-position of cyclohexene were critical for potency. Among them, compound 17a, bearing an N-(5-pyrazolyl-pyrimidin-2-yl)-cycloalkenyl- methylamine scaffold, exhibited excellent CETP inhibitory activity (IC50 = 0.07 μM) in vitro. Furthermore, it showed an acceptable pharmacokinetic profile in S-D rats and efficient HDL-C increase in high-fat fed hamsters.

  View details for DOI 10.1016/j.ejmech.2016.07.065

  View details for Web of Science ID 000385319000034

  View details for PubMedID 27490022

• Design, synthesis and biological evaluation of <i>N</i>,<i>N</i>-3-phenyl-3-benzylaminopropanamide derivatives as novel cholesteryl ester transfer protein inhibitor BIOORGANIC & MEDICINAL CHEMISTRY Zhao, D., Xie, H., Bai, C., Liu, C., Hao, C., Zhao, S., Yuan, H., Luo, C., Wang, J., Lin, B., Zheng, J., Cheng, M. 2016; 24 (8): 1589-1597

  View details for DOI 10.1016/j.bmc.2015.12.010

  View details for Web of Science ID 000372592900001

• Discovery of novel <i>N</i>,<i>N</i>-3-phenyl-3-benzylaminopropionanilides as potent inhibitors of cholesteryl ester transfer protein in vivo BIOORGANIC & MEDICINAL CHEMISTRY Xie, H., Li, Y., Bai, C., Wang, R., Liu, C., Hao, C., Lin, B., Cheng, M., Zhao, D. 2016; 24 (8): 1811-1818

  View details for DOI 10.1016/j.bmc.2016.03.002

  View details for Web of Science ID 000372592900023

• Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: potent agents restrain tumor cell growth and invasion ORGANIC & BIOMOLECULAR CHEMISTRY Hao, C., Li, X., Song, S., Guo, B., Guo, J., Zhang, J., Zhang, Q., Huang, W., Wang, J., Lin, B., Cheng, M., Li, F., Zhao, D. 2016; 14 (32): 7676-7690

  Abstract

  A new series of novel 1-phenanthryl-tetrahydroisoquinoline derivatives were designed, synthesized and biologically evaluated for their PAK4 inhibitory activities and anti-proliferative effects against three cancer cell lines A549, MCF-7 and HT-1080. Among them, compound 12a exhibited the most potent inhibitory activity against PAK4 with an IC50 value of 0.42 μM. Moreover, this compound inhibited the invasion of A549 tumor cells by regulating the PAK4-LIMK1-cofilin signaling pathway in vitro, and exhibited anti-tumor activity in vivo in the A549 tumor xenograft model. To further evaluate the binding mode of 12a with PAK4, the biotinylated 12a derivative has been synthesized and it was used for immunoprecipitation assay. Intriguingly, our observations suggest that 12a interacts with both the N- and C-termini of PAK4.

  View details for DOI 10.1039/c6ob01072e

  View details for Web of Science ID 000382059800009

  View details for PubMedID 27454186

• Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido propanoic acid derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26A1) BIOORGANIC & MEDICINAL CHEMISTRY Zhao, D., Sun, B., Ren, J., Li, F., Song, S., Lv, X., Hao, C., Cheng, M. 2015; 23 (6): 1356-1365

  Abstract

  All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36μM (compared to liarozole (IC50=2.45μM) and S8 (IC50=3.21μM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of β-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.

  View details for DOI 10.1016/j.bmc.2014.11.036

  View details for Web of Science ID 000349967600014

  View details for PubMedID 25684424

• Molecular recognition of CYP26A1 binding pockets and structure-activity relationship studies for design of potent and selective retinoic acid metabolism blocking agents JOURNAL OF MOLECULAR GRAPHICS & MODELLING Sun, B., Song, S., Hao, C., Huang, W., Liu, C., Xie, H., Lin, B., Cheng, M., Zhao, D. 2015; 56: 10-19

  Abstract

  All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A, plays a major role in the regulation of cellular differentiation and proliferation, and it is also an important pharmacological agent particularly used in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. However, ATRA is very easy to be metabolized into 4-hydroxyl-RA in vivo by CYP26A1, an inducible cytochrome P450 enzyme, eventually into more polar metabolites. Therefore, it is vital to develop specific retinoic acid metabolism blocking agents (RAMBAs) to inhibit the metabolic enzyme CYP26A1 in the treatment of relevant diseases aforementioned. In this study, CYP26A1 and its interactions with retinoic acid-competitive metabolism blocking agents were investigated by a combined ligand- and structure-based approach. First, since the crystal structure of CYP26A1 protein has not been determined, we constructed the 3D structure of CYP26A1 using homology modeling. In order to achieve a deeper insight into the mode of action of RAMBAs in the active site, the molecular superimposition model and the common feature pharmacophore model were constructed, and molecular docking was performed. The molecular superimposition model is composed of three features: the main chain groups, side chain groups, and azole groups. The common feature pharmacophore model consists of five chemical features: four hydrophobic groups and one hydrogen acceptor (HHHHA). The results of molecular docking show that the characteristic groups of RAMBAs were mapped into three different active pockets, respectively. A structure-activity relationship (SAR) was obtained by a combination of the molecular superimposition and docking results with the pharmacophore model. This study gives more insight into the interaction model inside the CYP26A1 active site and provides guidance for the design of more potent and possibly more selective RAMBAs.

  View details for DOI 10.1016/j.jmgm.2014.11.014

  View details for Web of Science ID 000350088600002

  View details for PubMedID 25541526

• Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors ORGANIC & BIOMOLECULAR CHEMISTRY Song, S., Li, X., Guo, J., Hao, C., Feng, Y., Guo, B., Liu, T., Zhang, Q., Zhang, Z., Li, R., Wang, J., Lin, B., Li, F., Zhao, D., Cheng, M. 2015; 13 (12): 3803-3818

  Abstract

  Functional versatility and elevated expression in cancers have promoted p21-activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug targets. In this study, a series of novel 1-phenanthryl-tetrahydroisoquinoline analogues have been designed and synthesized as a novel class of small-molecule PAK4 inhibitors to fit into the cavity of PAK4. All of the target compounds were evaluated for their in vitro PAK4 inhibitory activities and antiproliferative activities. Lead optimization identified all the derivatives with more potency than the lead compound, especially compound 21a. Moreover, compound 21a significantly induced the cell cycle in the G1/S phase, and inhibited migration and invasion of MCF-7 cells via the regulation of the PAK4-LIMK1-cofilin signaling pathway. A molecular modeling study showed possible novel binding modes between 21a and PAK4 and provided a structural basis for further structure-guided design of PAK4 inhibitors.

  View details for DOI 10.1039/c5ob00037h

  View details for Web of Science ID 000351352100034

  View details for PubMedID 25705811

• Pharmacophore-based design, synthesis, and biological evaluation of novel 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors CHINESE CHEMICAL LETTERS Zhao, D., Li, W., Shi, Y., Xiong, X., Song, S., Hao, C., Cheng, M., Shen, J. 2014; 25 (2): 299-304

  View details for DOI 10.1016/j.cclet.2013.11.033

  View details for Web of Science ID 000331857500027