Therapeutics: Src; v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1)

In vitro, zebrafish and mouse studies identified a selective pyrazolopyrimidine-based Src inhibitor that could help treat cancer. Chemical synthesis and in vitro testing of analogs of a promiscuous kinase inhibitor identified a compound that inhibited Src with an IC50 of less than 0.5 nM and exhibited about 2,000 times greater selectivity for Src over ABL1. In two human breast cancer cell lines, the compound inhibited proliferation with EC50 values of about 10 and 70 nM and decreased migration compared with the dual Src/ABL1 inhibitor Sprycel dasatinib or vehicle. In a xenograft mouse model of colon cancer, the compound decreased Src activity in the tumor compared with vehicle. In zebrafish embryos, the compound decreased Src-mediated migration of neuromasts in the mechanosensory system compared with vehicle without causing observable toxicity, whereas Sprycel or a dual Src/ABL1 inhibitor tool compound decreased neuromast migration and increased cardiotoxicity. Next steps could include testing the efficacy of the compound in tumor models...