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Protein tyrosine editing for the discovery of new molecular glues3 views
Author
Leace, David, Pharmacology - School of Medicine, University of Virginia
Advisors
Hsu, Ku-Lung, Chemistry and Pharmacology, University of Virginia
Abstract
Amino acids are frequently post translationally modified (phosphorylation, ubiquitination,
glycosylation, sulfonation etc.) inside of cells to alter protein conformation, enzymatic activity,
localization, and interaction networks. Small molecule drug discovery strategies have capitalized
on this machinery by developing covalent ligands that can “edit” essential amino acid residues to
modulate protein function for the treatment of disease. A subset of covalent ligands act as
monovalent molecular glues by stabilizing protein-protein interactions (PPIs). Here, we will
provide the first disclosure of tyrosine reactive molecular glues and their applications for
selective tumor killing, enzymatic inhibition, protein re-localization, and irreversible protein
crosslinking.
Chapter 1 introduces covalent small molecule drug discovery and its unique applications
to “undruggable” protein targets compared to traditional reversible therapeutics. In Chapter 2,
we will demonstrate how a tyrosine reactive enzymatic inhibitor for Glutathione S- Transferase
Pi (GSTP1) can be repurposed for molecular glue activity via a ligand induced protein tethering
(LIPT) mechanism. Electrophilic modification of tyrosines on GSTP1 results in disulfide
tethering of protein complexes in live cells and these neo-PPIs result in metabolic rewiring and
selective Leukemia cell killing. Chapter 3 will expand upon GSTP1 cell biology by showing
that GSTP1 can associate with both ribonucleoprotein (RNP) granules and RNA binding proteins
in response to cellular stress, and these interactions could be potentiated using LIPT. Chapter 4
expands tyrosine reactive chemistry to the enzyme class of protein tyrosine phosphatases (PTPs).
We identified a covalent inhibitor for SHP2 (DML189) with secondary molecular glue activity
via the LIPT mechanism. Chapter 5 discloses the first example of tyrosine-cysteine reactive
heterobifunctional crosslinkers and how they can be used to affect the interactome of enhancer of
mRNA decapping protein 3 (EDC3).
Leace, David. Protein tyrosine editing for the discovery of new molecular glues. University of Virginia, Pharmacology - School of Medicine, PHD (Doctor of Philosophy), 2025-11-26, https://doi.org/10.18130/gkey-pc02.
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