Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors

Abstract

Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound 8, a highly potent SHP2 allosteric inhibitor. X-ray studies showed novel stabilizing interactions with respect to known SHP2 inhibitors. Subsequent optimization allowed us to identify analogue 10, which possesses excellent potency and a promising PK profile in rodents.

PROTACs: A novel strategy for cancer drug discovery and development

“…Protein tyrosine phosphatase Src homology region 2‐containing protein tyrosine phosphatase 2 (SHP2) mutations in the Src homologous domain of the protein tyrosine phosphatase family exist in most tumor cells and are closely associated with cancer development and poor prognosis of cancer patients 214 , 215 by activating several proliferative signaling pathways for cancer occurrence. 216 Thus, SHP2 was proposed as an attractive target for cancer treatment.…”

Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors

“…Our quest to identify new potent and selective allosteric SHP2 inhibitors first led to the discovery of imidazopyrazine derivative 1 , as depicted in Figure (SHP2 IC 50 = 5 nM) . The subsequent supplementary exploration of the left-hand side (LHS) basic fragment using chemical-diversity-oriented libraries furnished trans -2-phenylpyrrolidine derivative 2 , shown in Figure , which exhibited promising human SHP2 inhibitory potency (SHP2 IC 50 = 225 nM).…”

“…7 Our quest to identify new potent and selective allosteric SHP2 inhibitors first led to the discovery of imidazopyrazine derivative 1, as depicted in Figure 2 (SHP2 IC 50 = 5 nM). 8 The subsequent supplementary exploration of the left-hand side (LHS) basic fragment using chemical-diversity-oriented libraries 9 furnished trans-2-phenylpyrrolidine derivative 2, shown in Figure 2, which exhibited promising human SHP2 inhibitory potency (SHP2 IC 50 = 225 nM). Hence, an attempt to optimize the novel amino moiety was undertaken with the following objectives: (a) maximize the SHP2 biochemical activity; (b) remove the secondary amine groups, which are potentially detrimental for cell penetration; (c) make the LHS portion properly constrained to likely control the metabolic stability.…”