SHP2(含有Src同源区2的蛋白酪氨酸磷酸酶2)是癌症治疗的目标,因为其在调节受体酪氨酸激酶(RTKs)下游的RAS/MAPK信号转导途径中起关键作用。此外,SHP2可以通过PD-1/PD-L1途径抑制T细胞。SHP2在许多生理和病理细胞过程中发挥关键作用,如细胞增殖,生存,和移民。
■这篇综述研究了从2018年至今在Espacenet和Scifinder数据库中公布的专利中报道的SHP2变构抑制剂。对要求保护的结构进行了概述,与SHP099相比,重点关注结构修饰,SHP099是第一个描述的SHP2的变构抑制剂。
■已经发现了多种强效变构SHP2抑制剂,披露,并在各种临床前癌症模型中进行了测试,具有强有力的有效性证据。15种化合物目前正在临床开发中,但它们都没有被批准用于营销。直到现在,由于获得性耐药机制和/或缺乏疗效,尚未证明SHP2抑制剂作为单一治疗药物的长期益处.然而,与多种药物联合治疗,比如MEK,BRAF,EGFR,RAS-G12C和PDL-1抑制剂,具有很高的潜力,目前是一个广泛的调查领域。
UNASSIGNED: SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is a target of interest for cancer therapy due to its key role in the regulation of the RAS/MAPK signal transduction pathway downstream of Receptor Tyrosine Kinases (RTKs). Moreover, SHP2 can inhibit T cells via the PD-1/PD-L1 pathway. SHP2 plays a critical role in numerous physiological and pathological cellular processes, such as cell proliferation, survival, and migration.
UNASSIGNED: This
review examines SHP2 allosteric inhibitors reported in patents published in Espacenet and Scifinder databases from 2018 to present. An overview of claimed structures is conducted, focusing attention on structural modifications compared to SHP099, the first described allosteric inhibitor of SHP2.
UNASSIGNED: Multiple potent allosteric SHP2 inhibitors have been discovered, disclosed, and tested in a variety of preclinical cancer models with strong evidence of efficacy. Fifteen compounds are currently in clinical development, but none of them have been approved for marketing. Until now, long-term benefit of SHP2 inhibitors as monotherapy agents have not been demonstrated due to acquired mechanisms of resistance and/or lack of efficacy. However, combination therapies with a variety of agents, such as MEK, BRAF, EGFR, RAS-G12C and PDL-1 inhibitors, have high potential and are currently an extensive area of investigation.