All Publications


  • Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety. Journal of medicinal chemistry Pandrala, M., Bruyneel, A. A., Hnatiuk, A. P., Mercola, M., Malhotra, S. V. 2022

    Abstract

    Development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective approach for the treatment of chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia. However, currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild type and mutant BCR-ABL kinase, including the "gatekeeper" T315I mutation that is resistant to all other currently available TKIs. However, it is one of the most cardiotoxic of the FDA-approved TKIs. Herein, we report the structure-guided design of a novel series of potent BCR-ABL inhibitors, particularly for the T315I mutation. Our drug design paradigm was coupled to iPSC-cardiomyocyte models. Systematic structure-activity relationship studies identified two compounds, 33a and 36a, that significantly inhibit the kinase activity of both native BCR-ABL and the T315I mutant. We have identified the most cardiac-safe TKIs reported to date, and they may be used to effectively treat CML patients with the T315I mutation.

    View details for DOI 10.1021/acs.jmedchem.1c01853

    View details for PubMedID 35944901

  • Reengineering Ponatinib to Minimize Cardiovascular Toxicity CANCER RESEARCH Hnatiuk, A. P., Bruyneel, A. N., Tailor, D., Pandrala, M., Dheeraj, A., Li, W., Serrano, R., Feyen, D. M., Vu, M. M., Amatya, P., Gupta, S., Nakauchi, Y., Morgado, I., Wiebking, V., Liao, R., Porteus, M. H., Majeti, R., Malhotra, S., Mercola, M. 2022; 82 (15): 2777-2791
  • Reengineering Ponatinib to Minimize Cardiovascular Toxicity. Cancer research Hnatiuk, A. P., Bruyneel, A. A., Tailor, D., Pandrala, M., Dheeraj, A., Li, W., Serrano, R., Feyen, D. A., Vu, M. M., Amatya, P., Gupta, S., Nakauchi, Y., Morgado, I., Wiebking, V., Liao, R., Porteus, M., Majeti, R., Malhotra, S. V., Mercola, M. 2022

    Abstract

    Small molecule Tyrosine Kinase Inhibitors (TKIs) have revolutionized cancer treatment and greatly improved patient survival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor of the BCR-ABL oncogene and is among the most cardiotoxic of TKIs. Consequently, use of ponatinib is restricted to the treatment of tumors carrying T315I-mutated BCR-ABL, which occurs in chronic myeloid leukemia (CML) and confers resistance to first- and second-generation inhibitors such as imatinib and nilotinib. Through parallel screening of cardiovascular toxicity and anti-tumor efficacy assays, we engineered safer analogs of ponatinib that retained potency against T315I BCR-ABL kinase activity and suppressed T315I mutant CML tumor growth. The new compounds were substantially less toxic in human cardiac vasculogenesis and cardiomyocyte contractility assays in vitro. The compounds showed a larger therapeutic window in vivo, leading to regression of human T315I mutant CML xenografts without cardiotoxicity. Comparison of the kinase inhibition profiles of ponatinib and the new compounds suggested that ponatinib cardiotoxicity is mediated by a few kinases, some of which were previously unassociated with cardiovascular disease. Overall, the study develops an approach using complex phenotypic assays to reduce the high risk of cardiovascular toxicity that is prevalent among small molecule oncology therapeutics.

    View details for DOI 10.1158/0008-5472.CAN-21-3652

    View details for PubMedID 35763671

  • Polypyridyl iridium(III) based catalysts for highly chemoselective hydrogenation of aldehydes JOURNAL OF CATALYSIS Pandrala, M., Resendez, A., Malhotra, S. V. 2019; 378: 283–88
  • Novel CMKLR1 Inhibitors for Application in Demyelinating Disease SCIENTIFIC REPORTS Kumar, V., LaJevic, M., Pandrala, M., Jacobo, S. A., Malhotra, S., Zabel, B. A. 2019; 9
  • Iridium(III) polypyridyl based new catalysts for highly chemoselective hydrogenation of adehydes Pandrala, M., Resendez, A., Malhotra, S. AMER CHEMICAL SOC. 2019
  • Quantitative Proteomic Profiling Reveals Key Pathways in the Anticancer Action of Methoxychalcone Derivatives in Triple Negative Breast Cancer JOURNAL OF PROTEOME RESEARCH Going, C. C., Tailor, D., Kumar, V., Birk, A. M., Pandrala, M., Rice, M. A., Stoyanova, T., Malhotra, S., Pitteri, S. J. 2018; 17 (10): 3574–85
  • Quantitative Proteomic Profiling Reveals Key Pathways in the Anticancer Action of Methoxychalcone Derivatives in Triple Negative Breast Cancer. Journal of proteome research Going, C. C., Tailor, D., Kumar, V., Birk, A. M., Pandrala, M., Rice, M. A., Stoyanova, T., Malhotra, S., Pitteri, S. J. 2018

    Abstract

    Triple negative breast cancer is an aggressive, heterogeneous disease with high recurrence and metastasis rates even with modern chemotherapy regimens and thus is in need of new therapeutics. Here, three novel synthetic analogues of chalcones, plant-based molecules that have demonstrated potency against a wide variety of cancers, were investigated as potential therapeutics for triple negative breast cancer. These compounds exhibit IC50 values of 5 muM in triple negative breast cancer cell lines and are more potent against triple negative breast cancer cell lines than against nontumor breast cell lines according to viability experiments. Tandem mass tag-based quantitative proteomics followed by gene set enrichment analysis and validation experiments using flow cytometry, apoptosis, and Western blot assays revealed three different anticancer mechanisms for these compounds. First, the chalcone analogues induce the unfolded protein response followed by apoptosis. Second, increases in the abundances of MHC-I pathway proteins occurs, which would likely result in immune stimulation in an organism. And third, treatment with the chalcone analogues causes disruption of the cell cycle by interfering with microtubule structure and by inducing G1 phase arrest. These data demonstrate the potential of these novel chalcone derivatives as treatments for triple negative breast cancer, though further work evaluating their efficacy in vivo is needed.

    View details for PubMedID 30200768

  • Design of deferasirox peptide-conjugated ligands for a selective delivery of anticancer Ti(IV) compounds Fernandez, L., Tinoco, A., Pandrala, M. AMER CHEMICAL SOC. 2018
  • Novel chalcone derivatives as potential therapeutic agents for triple negative breast cancer Kumar, V., Going, C., Tailor, D., Pandrala, M., Birk, A., Pitteri, S., Malhotra, S. AMER CHEMICAL SOC. 2018
  • Small molecules facilitating DNA repair in breast cancer cells Pandrala, M., Hastak, K., Kumar, V., Gardiner, M., Ford, J., Malhotra, S. AMER CHEMICAL SOC. 2018
  • Inhibiting guanylate binding protein 1 (GBP1) impedes ovarian cancer progression Tailor, D., Kumar, V., Pandrala, M., Resendez, A., Malhotra, S. V. AMER ASSOC CANCER RESEARCH. 2018
  • Studies to understand Ti(iV) speciation and transport in the human body Benjamin-Rivera, J., Tinoco, A., Delgado, Y., Pandrala, M., Vazquez, A., Vazquez, A. AMER CHEMICAL SOC. 2018
  • A ubiquitous metal, difficult to track: towards an understanding of the regulation of titanium(IV) in humans METALLOMICS Loza-Rosas, S. A., Saxena, M., Delgado, Y., Gaur, K., Pandrala, M., Tinoco, A. D. 2017; 9 (4): 346–56

    Abstract

    Despite the ubiquitous nature of titanium(iv) and several examples of its beneficial behavior in different organisms, the metal remains underappreciated in biology. There is little understanding of how the metal might play an important function in the human body. Nonetheless, a new insight is obtained regarding the molecular mechanisms that regulate the blood speciation of the metal to maintain it in a nontoxic and potentially bioavailable form for use in the body. This review surveys the literature on Ti(iv) application in prosthetics and in the development of anticancer therapeutics to gain an insight into soluble Ti(iv) influx in the body and its long-term impact. The limitation in analytical tools makes it difficult to depict the full picture of how Ti(iv) is transported and distributed throughout the body. An improved understanding of Ti function and its interaction with biomolecules will be helpful in developing future technologies for its imaging in the body.

    View details for DOI 10.1039/c6mt00223d

    View details for Web of Science ID 000399771300002

    View details for PubMedID 28164202

    View details for PubMedCentralID PMC5397357

  • Differential Anticancer Activities of the Geometric Isomers of Dinuclear Iridium(III) Complexes EUROPEAN JOURNAL OF INORGANIC CHEMISTRY Pandrala, M., Sundaraneedi, M. K., Ammit, A. J., Woodward, C. E., Wallace, L., Keene, F., Collins, J. 2015: 5694–5701
  • Chlorido-containing ruthenium(II) and iridium(III) complexes as antimicrobial agents DALTON TRANSACTIONS Pandrala, M., Li, F., Feterl, M., Mulyana, Y., Warner, J. M., Wallace, L., Keene, F., Collins, J. 2013; 42 (13): 4686–94

    Abstract

    A series of polypyridyl-ruthenium(II) and -iridium(III) complexes that contain labile chlorido ligands, [{M(tpy)Cl}(2){μ-bb(n)}](2/4+) {Cl-Mbb(n); where M = Ru or Ir; tpy = 2,2':6',2''-terpyridine; and bb(n) = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n = 7, 12 or 16)} have been synthesised and their potential as antimicrobial agents examined. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of the series of metal complexes against four strains of bacteria - Gram positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) - have been determined. All the ruthenium complexes were highly active and bactericidal. In particular, the Cl-Rubb(12) complex showed excellent activity against all bacterial cell lines with MIC values of 1 μg mL(-1) against the Gram positive bacteria and 2 and 8 μg mL(-1) against E. coli and P. aeruginosa, respectively. The corresponding iridium(III) complexes also showed significant antimicrobial activity in terms of MIC values; however and surprisingly, the iridium complexes were bacteriostatic rather than bactericidal. The inert iridium(III) complex, [{Ir(phen)(2)}(2){μ-bb(12)}](6+) {where phen = 1,10-phenanthroline) exhibited no antimicrobial activity, suggesting that it could not cross the bacterial membrane. The mononuclear model complex, [Ir(tpy)(Me(2)bpy)Cl]Cl(2) (where Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine), was found to aquate very rapidly, with the pK(a) of the iridium-bound water in the corresponding aqua complex determined to be 6.0. This suggests the dinuclear complexes [Ir(tpy)Cl}(2){μ-bb(n)}](4+) aquate and deprotonate rapidly and enter the bacterial cells as 4+ charged hydroxo species.

    View details for DOI 10.1039/c3dt32775b

    View details for Web of Science ID 000316294400045

    View details for PubMedID 23360972

  • Iridium(III) Complexes Containing 1,10-Phenanthroline and Derivatives: Synthetic, Stereochemical, and Structural Studies, and their Antimicrobial Activity AUSTRALIAN JOURNAL OF CHEMISTRY Pandrala, M., Li, F., Wallace, L., Steel, P. J., Moore, B., Autschbach, J., Collins, J., Keene, F. 2013; 66 (9): 1065–73

    View details for DOI 10.1071/CH13264

    View details for Web of Science ID 000324210400010