The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro. Suppression of Erk phopsphorylation by the lead compound is also consistent with SHP2 inhibition in AML cells. Our findings provide an alternative starting point for therapeutic intervention and will catalyze investigations into the relationship between SHP2 conformational regulation, activity, and disease progression.

PTPN11癌基因编码细胞质蛋白酪氨酸磷酸酶SHP2，通过其在多种信号通路中的作用，促进血液系统恶性肿瘤和其他癌症的进展。在这里，我们采用高通量筛选来发现一种主要的化学支架，即苯并噻唑并嘧啶酮，该构架通过同时参与C-SH2和PTP结构域来变构地抑制这种致癌性磷酸酶。我们改进了线索，以生成在体外可更好抑制SHP2活性的类似物。铅化合物抑制Erk磷酸化也与AML细胞中SHP2的抑制作用相一致。我们的发现为治疗干预提供了另一个起点，并将促进对SHP2构象调控，活性和疾病进展之间关系的研究。