Structure-Based Design, Synthesis, and Evaluation of Novel Ponatinib Derivatives With a Significantly Altered Selectivity Profile

Abstract

The protein kinase inhibitor ponatinib is an approved anti-cancer drug that remains effective even against kinases with gate keeper residue mutations. However, serious toxic side effects, particularly cardiotoxicity, prevent its widespread therapeutic use. The undesirable side effects have been attributed to non-selective inhibition of more than 60 kinases from both the tyrosine and serine/threonine kinase families. With the aim of greatly reducing the spectrum of inhibited kinases, we performed structure based design and synthesis of novel ponatinib derivatives. By modifying the methylation pattern of the central benzamide ring and replacing the N-methylpiperazine end group with a propenylamine or propylamine chain, we discovered compound 5 displaying a significantly altered target kinase profile, with B-Raf and Flt-1 being its main targets. This specific target combination has not yet been described for a kinase inhibitor. Furthermore, two of the original off-target kinases that should not be inhibited to avoid cardiotoxicity, SLK and FGFR1, were no longer affected by 5. Interestingly, 5 almost completely retained the efficacy of ponatinib in inhibiting colony formation by MDA-MB-231 breast cancer cells. These results might support the development of novel pona tinib analogs toward therapeutic kinase inhibitors with improved pharmacological properties.