Advancing the development of HUWE1 inhibitors for cancer treatment

HUWE1 is a HECT-family E3 ubiquitin ligase that regulates key oncogenic pathways including protein quality control, apoptosis, and DNA damage response. It is overexpressed in multiple cancers such as breast and lung carcinoma, and pancreatic adenocarcinoma, with high expression correlating with poor prognosis. Functional studies and DepMap analyses reveal that ~35% of cancer cell lines, especially invasive breast carcinoma and mesothelioma, are dependent on HUWE1 for survival. Unlike many cancer driver genes, HUWE1 is dispensable in most somatic tissues, indicating a favorable therapeutic window. Our recent discovery of HUWE1’s “Ubiquitin-Directed Ubiquitin Ligase” activity underscores its unique role in proteostasis and tumor maintenance.

Despite its biological significance, HUWE1 remains an untapped therapeutic target. We have developed selective small-molecule inhibitors that disrupt HUWE1’s catalytic functions, leading to targeted cancer cell suppression while sparing HUWE1-independent cells.  Using Cryo-EM, we identified the drug binding site and elucidated the mechanism of action. Given HUWE1’s central role in regulating multiple cancer-relevant pathways, targeting HUWE1 could enable a novel therapeutic strategy that exploits cancer-specific vulnerabilities, especially in tumors with limited treatment options.

This study aims to advance the development of a potent and selective HUWE1 inhibitor, with a goal to identify the lead molecule through structure-based compound optimization and functional studies. We will (1) determine the binding affinity of these compounds with HUWE1 using biophysical methods; (2) validate the drug binding pocket, and perform structure-based optimization to significantly improve potency of the inhibitor, and characterize the molecule.