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Issue 4, 2020

Phosphotyrosine isosteres: past, present and future

Author affiliations

Abstract

Tyrosine phosphorylation is a critical component of signal transduction for multicellular organisms, particularly for pathways that regulate cell proliferation and differentiation. While tyrosine kinase inhibitors have become FDA-approved drugs, inhibitors of the other important components of these signaling pathways have been harder to develop. Specifically, direct phosphotyrosine (pTyr) isosteres have been aggressively pursued as inhibitors of Src homology 2 (SH2) domains and protein tyrosine phosphatases (PTPs). Medicinal chemists have produced many classes of peptide and small molecule inhibitors that mimic pTyr. However, balancing affinity with selectivity and cell penetration has made this an extremely difficult space for developing successful clinical candidates. This review will provide a comprehensive picture of the field of pTyr isosteres, from early beginnings to the current state and trajectory. We will also highlight the major protein targets of these medicinal chemistry efforts, the major classes of peptide and small molecule inhibitors that have been developed, and the handful of compounds which have been tested in clinical trials.

Graphical abstract: Phosphotyrosine isosteres: past, present and future

Article information


Submitted
12 Sep 2019
Accepted
18 Nov 2019
First published
18 Nov 2019

Org. Biomol. Chem., 2020,18, 583-605
Article type
Review Article
Author version available

Phosphotyrosine isosteres: past, present and future

R. A. Cerulli and J. A. Kritzer, Org. Biomol. Chem., 2020, 18, 583 DOI: 10.1039/C9OB01998G

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