Synthesis and biological evaluation of heterocyclic bis-aryl amides as novel Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors. Issue 11 (1st June 2020)

• Record Type: Journal Article
• Authors: Satheeshkumar, Rajendran; Zhu, Rui; Feng, Bo; Huang, Chao; Gao, Ya; Gao, Li-Xin; Shen, Chao; Hou, Ting-Jun; Xu, Lei; Li, Jia; Zhu, Yun-Long; Zhou, Yu-Bo; Wang, Wen-Long
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 11(2020)
• Publication Date: 2020-06-01
• Subjects: Heterocyclic bis-aryl amides -- PTP1B -- SHP2 -- Inhibitors -- Structure-activity relationships (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127170
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. Consequently, SHP2 has emerged as a compelling target for novel anti-cancer agents. Replacing one of phenyl ring in PTP1B inhibitor 1 with heterocyclic ring led to a series of heterocyclic bis-aryl amide derivatives. The representative compound 7b displayed SHP2 inhibitory activity with IC50 of 2.63 ± 0.08 μM, exhibited about 4-fold selectivity for SHP2 over TCPTP and had no detectable activity against SHP1 and PTP1B. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors with optimal potency and improved pharmacological properties.