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Nicotinamide-Ponatinib, HSN748, a Potent Anti-CML and Anti-AML Compound with Better Kinase Selectivity than Ponatinib

preprint
submitted on 10.11.2018 and posted on 13.11.2018 by Elizabeth Larocque, Nimmashetti Naganna, Herman Sintim

Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET and FGFRs, it is also being evaluated against AML, biliary and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity could be better tolerated. A nicotinamide analog of ponatinib, HSN748, retains activity against FLT3, ABL1, VEGFRs and PDGFRa/b but losses activity against c-Src, FGFRs and P38a. Since Src or FGFR inhibitions are known to lead to platelet disfunction or cardiovascular toxicities respectively, HSN748 might have a better safety profile than ponatinib and deserves further evaluation as a possible CML or AML therapeutic.

History

Email Address of Submitting Author

hsintim@purdue.edu

Institution

Purdue University

Country

US

ORCID For Submitting Author

0000-0002-2280-9359

Declaration of Conflict of Interest

HOS is a co-founder of KinaRx LLC, a start-up company interested in developing therapies for malignant neoplastic diseases.

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