Emerging chemical scaffolds with potential SHP2 phosphatase inhibitory capabilities - A comprehensive review.

Abstract

The drug discovery panorama is cluttered with promising therapeutic targets that have been deserted because of inadequate authentication and screening failures. Molecular targets formerly tagged as "undruggable" are nowadays being more cautiously cross-examined, and whilst they stay intriguing, numerous targets are emerging more accessible. Protein tyrosine phosphatases (PTPs) excellently exemplifies a class of molecular targets that have transpired as druggable, with several small molecules and antibodies recently turned available for further development. In this respect, SHP2, a PTP, has emerged as one of the potential targets in the current pharmacological research, particularly for cancer, due to its critical role in various signalling pathways. Recently, few molecules with excellent potency have entered clinical trials, but none could reach the clinic. Consequently, search for novel, non-toxic, and specific SHP2 inhibitors are on purview. In this review, general aspects of SHP2 including its structure and mechanistic role in carcinogenesis have been presented. It also sheds light on the development of novel molecular architectures belonging to diverse chemical classes that have been proposed as SHP2-specific inhibitors along with their structure-activity relationships (SARs), stemming from chemical, mechanism-based and computer-aided studies reported since January 2015 to July 2020 (excluding patents), focusing on their potency and selectivity. The encyclopedic facts and discussions presented herein will hopefully facilitate researchers to design new ligands with better efficacy and selectivity against SHP2.