Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Abstract

Protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation which affects a myriad of cellular processes. Imbalance in signal pathways mediated by PTPs has been associated with development of many human diseases including cancer, metabolic, and immunological diseases. Several compelling evidence suggest that many members of PTP family are novel therapeutic targets. However, the clinical development of conventional PTP-based active-site inhibitors originally was hampered by the poor selectivity and pharmacokinetic properties. In this regard, PTPs has been widely dismissed as "undruggable." Nonetheless, allosteric modulation has become increasingly an influential and alternative approach that can be exploited for drug development against PTPs. Unlike active-site inhibitors, allosteric inhibitors exhibit a remarkable targetselectivity, drug-likeness, potency, and in vivo activity. Intriguingly, there has been a high interest in novel allosteric PTPs inhibitors within the last years. In this review, we focus on the recent advances of allosteric inhibitors that have been explored in drug discovery and have shown an excellent result in the development of PTPs-based therapeutics. A special emphasis is placed on the structure-activity relationship and molecular

Discovery of Novel Small-Molecule Scaffolds for the Inhibition and Activation of WIP1 Phosphatase from a RapidFire Mass Spectrometry High-Throughput Screen

“…However, these enzymes, once considered undruggable, are more frequently pursued in drug development. 7,75 WIP1 phosphatase, as a critical actor in the DNA damage response pathway, is a prime candidate for drug development. 76 While HTS campaigns targeting phosphatases generally aim at discovering a single kind of modulator, WIP1 is unusual, as evidence suggests that either inhibiting or activating WIP1 might be a viable pharmacologic strategy, depending on the P53 status of tumor cells.…”

“…Therefore, kinases and phosphatases have long been considered as therapeutic targets, especially in cancer. , While drug development for kinase modulation has been immensely successful in the past 20 years, particularly in the field of oncology, it has been more challenging to target phosphatases. However, these enzymes, once considered undruggable, are more frequently pursued in drug development. , WIP1 phosphatase, as a critical actor in the DNA damage response pathway, is a prime candidate for drug development . While HTS campaigns targeting phosphatases generally aim at discovering a single kind of modulator, WIP1 is unusual, as evidence suggests that either inhibiting or activating WIP1 might be a viable pharmacologic strategy, depending on the P53 status of tumor cells. − , …”

Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

“…The sequence and function of PTP domain is evolutionarily conserved, making SHP2 share a conserved catalytic mechanism with other members in PTPs family 23 . The overall fold of PTP catalytic domain (residues 221–525) is consisted of approximate 300 amino acid residues in conjunction with a panel of defined loop regions (Figure 2B).…”

“…The sequence and function of PTP domain is evolutionarily conserved, making SHP2 share a conserved catalytic mechanism with other members in PTPs family. 23 The overall fold of PTP catalytic domain (residues 221-525) is consisted of approximate 300 amino acid residues in conjunction with a panel of defined loop regions (Figure 2B). It is functionally classified into two types: (1) fundamental loop regions contain the pTyr recognition loop (pTyr-loop), WPD loop and P loop, which corporately assist substrate turnover; (2) assistant loop regions include the E loop and Q loop, which mainly accommodate the fundamental loop to increase the affinity of pTyr-containing substrate and stabilize the conformation transition of SHP2.…”

Selective Inhibition of PTP1B by New Anthraquinone Glycosides from Knoxia valerianoides

“…PTP1B acts as a key negative regulator of insulin signaling by dephosphorylating insulin receptor and its effector proteins . Mounting evidence provides a high level of validation for PTP1B as a therapeutic target for diabetes. , Nevertheless, due to the highly conserved active site of PTPs with a positively charged binding surface, the designed phosphotyrosine (pTyr) mimetics generally suffer from poor selectivity and membrane permeability . Alternatively, the PTP1B inhibitors targeting the allosteric sites that are remote from the active site, and that feature hydrophobic binding surfaces and less conserved residues, display enhanced specificity and oral bioavailability. − These allosteric inhibitors show high selectivity over T-cell protein tyrosine phosphatase (TCPTP) that is the closest homologue to PTP1B but has distinct physiological functions .…”