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.

Energetic and Geometric Characteristics of the Substituents: Part 2: The Case of NO2, Cl, and NH2 Groups in Their Mono-Substituted Derivatives of Simple Nitrogen Heterocycles

“…Six-membered nitrogen heterocycles are an important subject of research due to their importance in organic, bioorganic, and medicinal chemistry [1,2]. They are widely used as pharmaceuticals, agrochemicals, and natural products [3][4][5]. In addition to their use as ligands for complexing metals [6], they are valuable in the target-oriented synthesis of biologically active molecules [7][8][9][10] and new materials [11].…”

Role of SHP2/PTPN11 in the occurrence and prognosis of cancer: A systematic review and meta‑analysis

“…PTP catalyzes the dephosphorylation of phosphotyrosine and is a key control mechanism in mammalian signal transduction ( 11 ). Aberrant expression levels of SHP2/PTPN11 have been reported to promote a number of diseases, including types of cancer, diabetes and autoimmune diseases ( 29 ). SHP2/PTPN11 is involved in the regulation of various signaling pathways, such as Ras/ERK, Janus kinase/STAT, PI3K/AKT and NF-κB.…”

In Silico Study of Physicochemical Characteristics and Anticancer Potential of Peptides Derived from Salvia Hispanica

“…Active mutants of SHP2 have been identi ed in patients with juvenile myelomonocytic leukemia, acute myelogenous leukemia, and certain types of solid tumors, such as lung and colon cancer (H.-C. . Recent studies have explored the inhibition mechanism of this enzyme and interactions with certain amino acid residues from its allosteric site 1, allosteric site 2, P-loop and Q-loop are speculated to be key to lead to the autoinhibition conformation of SHP2 (Song et al, 2014;Tripathi & Ayyannan, 2021). The residue Thr108 belongs to the allosteric site 1, to which the PAPs evaluated in this study were xed into to obtain potential binding simulations.…”