{Reference Type}: Journal Article
{Title}: Structural study of ponatinib in inhibiting SRC kinase.
{Author}: Guo M;Duan Y;Dai S;Li J;Chen X;Qu L;Chen Z;Wei H;Jiang L;Chen Y;
{Journal}: Biochem Biophys Res Commun
{Volume}: 598
{Issue}: 0
{Year}: 04 2022 2
{Factor}: 3.322
{DOI}: 10.1016/j.bbrc.2022.02.001
{Abstract}: Ponatinib is a multi-target tyrosine kinase inhibitor that targets ABL, SRC, FGFR, and so on. It was designed to overcome the resistance of BCR-ABL mutation to imatinib, especially the gatekeeper mutation ABLT315I. The molecular mechanism by which ponatinib overcomes mutations of BCR-ABL and some other targets has been explained, but little information is known about the characteristics of ponatinib binding to SRC. Here, we showed that ponatinib inhibited wild type SRC kinase but failed to inhibit SRC gatekeeper mutants in both biochemical and cellular assays. We determined the crystal structure of ponatinib in complex with the SRC kinase domain. In addition, by structural analysis, we provided a possible explanation for why ponatinib showed different effects on SRC and other kinases with gatekeeper mutations. The resistance mechanism of SRC gatekeeper mutations to ponatinib may provide meaningful information for designing inhibitors against SRC family kinases in the future.