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.

Src激酶（SRC）是多种信号通路的关键调控因子，且在癌症发生发展中发挥重要作用。然而，选择性Src激酶抑制剂的研发颇具挑战，目前获美国食品药品监督管理局（FDA）批准的Src激酶抑制剂达沙替尼（dasatinib）与博舒替尼（bosutinib）均为多靶点激酶抑制剂。本文详述了我们通过靶向Src激酶P环（P-loop）上的半胱氨酸277（cysteine 277），开发选择性Src共价抑制剂的研究工作。本研究以混杂型共价激酶抑制剂（promiscuous covalent kinase inhibitor, CKI）SM1-71作为起始模板，成功开发出共价抑制剂15a，该化合物可将Src激酶与SM1-71的其他共价靶点（如TAK1、FGFR1）区分开来。作为不可逆共价抑制剂，化合物15a在体外与体内均展现出对Src激酶信号通路的持续抑制作用。此外，15a在携带Src激酶激活特征的非小细胞肺癌细胞系中表现出强效的抗增殖活性，由此证明该研发策略有望为后续药物开发提供可靠方向。