靶向SHP2^(E76A)突变体的小分子降解剂有效抑制野生型和突变体SHP2肿瘤细胞增殖

Small Molecule Degraders Targeting the SHP2^(E76A) Mutant Effectively Inhibiting the Proliferation of Wild-type and Mutant SHP2 Dependent Tumor Cells

SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)是由Ptpn11基因编码的非受体型蛋白酪氨酸磷酸酶,通过RAS (rat sarcoma)-ERK (extracellular regulated protein kinases)信号通路的活化调控细胞生长、分化和凋亡,并参与PD-1 (programmed cell death protein 1)/PD-L1(programmed cell death ligand 1)通路的免疫监控,已成为有突破意义的抗癌药物新靶标.靶向SHP2变构位点的抑制剂通过稳定SHP2非活性构象而抑制磷酸酶催化功能,具有很好的成药性.但是,SHP2功能获得性突变(gainoffunction,简称GOF)导致一系列发育障碍疾病和肿瘤的发生,并对SHP2野生型变构抑制剂产生耐药性.本工作首次以靶向SHP2激活突变体的变构抑制剂为靶头,基于PROTACs(proteolysis-targeting chimeras)技术,设计合成了一系列全新SHP2小分子降解剂.其中先导化合物3f和4d保持了对突变型SHP2^(E76A)的酶抑制活性,而且对于野生型SHP2依赖的人食管鳞癌细胞KYSE-520和突变型SHP2^(N58S)人大细胞肺癌细胞NCI-H661都显示强效抗增殖活性,比相应变构抑制剂的活性提高了5~10倍,为治疗SHP2突变或活化导致的遗传性疾病或肿瘤提供了新的干预策略.

Src homology 2 domain-containing protein tyrosine phosphatase 2(SHP2)is a non-receptor protein tyrosine phosphatase encoded by the Ptpn11 gene.SHP2 regulates cell growth,differentiation and apoptosis via modulating various signaling pathways,such as RAS/ERK signaling pathway,and participates in the PD-1/PD-L1 pathway governing immune surveillance,thus has been recognized as a breakthrough antitumor therapeutic target.By stabilizing the inactive closed conformation of SHP2,allosteric inhibitors have overcome the druggability issues and advanced to clinical trials.However,the gain-of-function mutation(GOF)of the Ptpn11 gene renders SHP2 in a pathological active conformation,causing a range of developmental disorders and tumors.Overactivated SHP2 mutants undergo structural and functional changes,conferring resistance to SHP2 wild-type allosteric inhibitors.Therefore,developing novel therapeutic modality that effectively inhibits pathogenic SHP2 mutants has become an urgent need for the treatment of SHP2 related diseases.Herein,we report the design,synthesis and biological evaluation of novel SHP2 small molecule degraders based on PROTACs(proteolysis-targeting chimeras)technology by employing an allosteric inhibitor 2 targeting SHP2-activated mutant as the warhead.These SHP2^(E76A) PROTACs have shown strong inhibitory activities in both enzyme and cell proliferation.Notably,the lead compounds 3f and 4d exhibit potent antiproliferative activities against both the wild-type SHP2 dependent human esophageal squamous carcinoma cell line KYSE-520 and the mutant SHP2^(N58S) human large-cell lung carcinoma cell line NCI-H661,with an improvement by 5 to 10-fold compared to the positive control 2.This study provides a new therapeutic intervention strategy for treating developmental disorders and tumors caused by SHP2 mutation or activation.