Abstract LB077: Reengineering ponatinib to minimize cardiovascular toxicity

Abstract

Abstract Introduction and Purpose of the Study: The advent of small molecule Tyrosine Kinase Inhibitors (TKIs) has revolutionized cancer treatment and greatly improved patient survival. However, the life-threatening cardiovascular toxicity of many TKIs present major concerns. Ponatinib is the most effective treatment for patients harboring the common T315I mutation of BCR-ABL that drives Chronic Myeloid Leukemia (CML) yet is one of the most cardiotoxic of TKIs. Ponatinib-induced events include myocardial infarction, heart failure, stroke, peripheral vascular disease and venous thrombosis. The aim of this study is to reengineer the chemical structure of ponatinib to minimize its adverse cardiovascular effects by using in vitro and in vivo models of cardiovascular toxicity. Experimental Procedures: We developed in vitro cardiovascular toxicity assays using human iPSC-cardiomyocytes (hiPSC-CMs) and human microvascular endothelial cells (HMVECs), and assessed anti-tumor efficacy in T315I mutated K562 CML cells. The cardiotoxicity was determined by impairment of cardiomyocyte contractility function, the vascular toxicity was defined by inability to form capillary-like networks in vasculogenesis assays. In vitro screening of ponatinib analogues probed chemical moieties responsible for its cardiovascular toxicity that were confirmed using mice xenograft mice models with human T315I mutant K562 cells. Summary of Unpublished Data: Compared to ponatinib, refined analogues showed markedly decreased adverse effects on HMVECs vasculogenesis and hiPSC-CMs contractility in vitro. The therapeutic window was increased in vivo, leading to regression of human T315I mutant CML xenografts comparable to ponatinib but without increasing serum levels of cardiac troponin. The kinase inhibition profiles of the “safe” analogues compared to ponatinib identified candidate mediators of ponatinib-induced toxicity. Validation by selective knockdown revealed likely mediators of cardiotoxicity, including FGFR. Conclusions: We succeeded in engineering a cardiovascular safe TKI that retained effective therapeutic properties against BCR-ABL T351 mutated form of CML, but with substantially decreased cardiovascular toxicity. Citation Format: Anna Pavlovna Hnatiuk, Arne A. Bruyneel, Dhanir Taylor, Mallesh Pandrala, Arpit Dheeraj, Wendy Li, Ricardo Serrano Fernandez, Dries A. Feyen, Michelle M. Wu, Prashila Amatya, Isabel Morgado, Volker Wiebking, Matthew H. Porteus, Sanjay Malhotra, Mark Mercola. Reengineering ponatinib to minimize cardiovascular toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB077.