Drugging the undruggable

Therapeutic potential of targeting protein tyrosine phosphatases

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

CONSPECTUS: Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positivecharged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmune disorders, and tuberculosis. We hope that these results will help dispel concerns about the druggability of PTPs and entice further effort in fostering a PTP-based drug discovery enterprise. Well-characterized, potent, selective and bioactive inhibitors are essential tools for functional interrogation of PTPs in disease biology and target validation. They will also play a critical role in illuminating the druggability of PTPs and provide the groundwork for new therapies for the treatment of human diseases.

Original languageEnglish (US)
Pages (from-to)122-129
Number of pages8
JournalAccounts of Chemical Research
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Protein Tyrosine Phosphatases
Phosphorylation
Tyrosine
Medical problems
Oncology
Cell membranes
Metabolism
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Drugging the undruggable : Therapeutic potential of targeting protein tyrosine phosphatases. / Zhang, Zhong-Yin.

In: Accounts of Chemical Research, Vol. 50, No. 1, 01.01.2017, p. 122-129.

Research output: Contribution to journalArticle

@article{7109d9fe027b4756b29d89d400ccafd6,
title = "Drugging the undruggable: Therapeutic potential of targeting protein tyrosine phosphatases",
abstract = "CONSPECTUS: Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as {"}undruggable{"}, due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positivecharged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmune disorders, and tuberculosis. We hope that these results will help dispel concerns about the druggability of PTPs and entice further effort in fostering a PTP-based drug discovery enterprise. Well-characterized, potent, selective and bioactive inhibitors are essential tools for functional interrogation of PTPs in disease biology and target validation. They will also play a critical role in illuminating the druggability of PTPs and provide the groundwork for new therapies for the treatment of human diseases.",
author = "Zhong-Yin Zhang",
year = "2017",
month = "1",
day = "1",
doi = "10.1021/acs.accounts.6b00537",
language = "English (US)",
volume = "50",
pages = "122--129",
journal = "Accounts of Chemical Research",
issn = "0001-4842",
publisher = "American Chemical Society",
number = "1",

}

TY - JOUR

T1 - Drugging the undruggable

T2 - Therapeutic potential of targeting protein tyrosine phosphatases

AU - Zhang, Zhong-Yin

PY - 2017/1/1

Y1 - 2017/1/1

N2 - CONSPECTUS: Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positivecharged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmune disorders, and tuberculosis. We hope that these results will help dispel concerns about the druggability of PTPs and entice further effort in fostering a PTP-based drug discovery enterprise. Well-characterized, potent, selective and bioactive inhibitors are essential tools for functional interrogation of PTPs in disease biology and target validation. They will also play a critical role in illuminating the druggability of PTPs and provide the groundwork for new therapies for the treatment of human diseases.

AB - CONSPECTUS: Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positivecharged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmune disorders, and tuberculosis. We hope that these results will help dispel concerns about the druggability of PTPs and entice further effort in fostering a PTP-based drug discovery enterprise. Well-characterized, potent, selective and bioactive inhibitors are essential tools for functional interrogation of PTPs in disease biology and target validation. They will also play a critical role in illuminating the druggability of PTPs and provide the groundwork for new therapies for the treatment of human diseases.

UR - http://www.scopus.com/inward/record.url?scp=85021665675&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021665675&partnerID=8YFLogxK

U2 - 10.1021/acs.accounts.6b00537

DO - 10.1021/acs.accounts.6b00537

M3 - Article

VL - 50

SP - 122

EP - 129

JO - Accounts of Chemical Research

JF - Accounts of Chemical Research

SN - 0001-4842

IS - 1

ER -