Reengineering Ponatinib to Minimize Cardiovascular Toxicity

Anna P. Hnatiuk, Arne A.N. Bruyneel, Dhanir Tailor, Mallesh Pandrala, Arpit Dheeraj, Wenqi Li, Ricardo Serrano, Dries A.M. Feyen, Michelle M. Vu, Prashila Amatya, Saloni Gupta, Yusuke Nakauchi, Isabel Morgado, Volker Wiebking, Ronglih Liao, Matthew H. Porteus, Ravindra Majeti, Sanjay V. Malhotra, Mark Mercola

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Small molecule tyrosine kinase inhibitors (TKI) 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 secondgeneration inhibitors such as imatinib and nilotinib. Through parallel screening of cardiovascular toxicity and antitumor 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.

Original languageEnglish (US)
Pages (from-to)2777-2791
Number of pages15
JournalCancer Research
Volume82
Issue number15
DOIs
StatePublished - Aug 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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