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 gatekeeper 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‐methylpiperazine end group with a propenylamine or propylamine chain, we discovered compounddisplaying 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. Interestingly,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 ponatinib analogs toward therapeutic kinase inhibitors with improved pharmacological properties. We developed new derivatives of the cancer drug ponatinib, significantly reducing and altering its spectrum of target kinases. Compoundretained the efficacy in inhibiting the colony formation of MDA‐MB‐231 cells and acted primarily on B‐Raf and Flt‐1 as its main targets in a kinase panel. A modification option was also identified to add or remove SPRK1 as an additional target. graphical