[R01] Assay Development and Screening for Discovery of UBR2 Chemical Probes
Ente: National Cancer Institute
Scadenza: 2029-06-30
Importo max: 663.196 EUR
Paese: US
Descrizione
Project Summary/Abstract
This application is in response to PAR-25-153 “Assay development and screening for discovery
of chemical probes, drugs or immunomodulators” to discover novel chemical probes for a ubiquitin
E3 ligase, UBR2, which has been established as a target to develop treatment for cancer and
diabetes-induced cachexia. Cachexia, characterized by involuntary muscle loss occurring with
cancer, diabetes, and other chronic illnesses, severely impacts the lifespan and quality of life of
patients. Despite more than two decades of effort, there is still no effective therapy for cachexia.
Therefore, addressing this well-established mechanism to develop treatment for cachexia is
necessary to address the high unmet medical needs. Aim 1 will develop HTS-compatible (1536-
well) assays for UBR2 and its close homolog UBR1 to ensure discovery of UBR2 selective ligands.
Aim 2 will implement and complete a UBR2 screen on ~10K compounds selected from an
Enamine REAL library representing a broad sampling of chemical space linked to millions of
analogs accessible by robotic synthesis. We will validate hits and test the top hits for reversal of
cachexia. Aim 3 will determine the mechanism of novel validated hits by X-ray crystallography
and perform iterative cycles of structure-guided ligand discovery. We employ scientifically
rigorous approaches, including highly sensitive, quantitative, and reproducible biophysical and
cellular assays in combination with a relevant and established disease model, to develop novel
UBR2 ligands with favorable pharmacological properties that will facilitate future translational
studies. In addition, we provide the molecular mechanism of ligand binding by X-ray
crystallography to rationally design and optimize ligands. Our extensive preliminary data,
including assay development and solving multiple high-resolution co-crystal structures of UBR1
and UBR2 with their ligands, demonstrates feasibility. Notably, the two PIs have a history of
successful collaboration, ensuring successful execution of the proposed studies.
Istituzione: UNIVERSITY OF CALIFORNIA, SAN DIEGO
PI: THOMAS D Y CHUNG, Yuan Chen
Progetto: 1R01CA315210-01
Settori: National Cancer Institute
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