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

13 November 2018, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

Nicotinamide ponatinib
AML,
CML
Kinase inhibitor
RET
FLT3
ABL1(T315I)
FGFR
VEGFR
Src

Supplementary materials

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Description
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Title
HSN748-Manuscript
Description
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