Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P‑Loop Cysteine

SRC
is a major regulator of many signaling pathways and contributes
to cancer development. However, development of a selective SRC inhibitor
has been challenging, and FDA-approved SRC inhibitors, dasatinib and
bosutinib, are multitargeted kinase inhibitors. Here, we describe
our efforts to develop a selective SRC covalent inhibitor by targeting
cysteine 277 on the P-loop of SRC. Using a promiscuous covalent kinase
inhibitor (CKI) SM1-71 as a starting point, we developed
covalent inhibitor 15a, which discriminates SRC from
other covalent targets of SM1-71 including TAK1 and FGFR1.
As an irreversible covalent inhibitor, compound 15a exhibited
sustained inhibition of SRC signaling both in vitro and in vivo. Moreover, 15a exhibited
potent antiproliferative effects in nonsmall cell lung cancer cell
lines harboring SRC activation, thus providing evidence that this
approach may be promising for further drug development efforts.