Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor

• Published in: Acta pharmaceutica Sinica. B Vol. 14; no. 8; pp. 3624 - 3642
• Main Authors: Tang, Kai, Wang, Shu, Feng, Siqi, Yang, Xinyu, Guo, Yueyang, Ren, Xiangli, Bai, Linyue, Yu, Bin, Liu, Hong-Min, Song, Yihui
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2024; Elsevier
• Subjects: Esophageal cancer; Original; Protein tyrosine phosphatase; Pyrazolopyrazine; SHP2 inhibitor; Pyrazolopyrazine; SHP2 inhibitor; Protein tyrosine phosphatase; Esophageal cancer
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2024.03.028

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the “tunnel” allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer. Pyrazolopyrazine-based TK-642 is identified as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5 %; t1/2 = 2.47 h). [Display omitted]