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Published on: July 17, 2020
Discovery of CHD1 Antagonists for PTEN-Deficient Prostate Cancer
Rebecca L Johnson1, Amanda L Graboski2, Fengling Li3
1Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Abstract:
CHD1 is a chromodomain-helicase DNA-binding protein that preferentially recognizes di- and trimethylated lysine 4 on histone H3 (H3K4me2/3). Genetic studies have established CHD1 as a synthetic lethal target in phosphatase and tensin homologue (PTEN)-deficient cancers. Despite this attractive therapeutic link, no inhibitors or antagonists of CHD1 have been reported to date. Herein, we report the discovery of UNC10142, a first-in-class small molecule antagonist of the tandem chromodomains of CHD1 that binds with an IC50 of 1.7 ± 0.2 μM. A cocrystal structure revealed a unique binding mode and competition pull-down experiments in cell lysates confirmed endogenous target engagement. Treatment of PTEN-deficient prostate cancer cells with UNC10142 led to a dose-dependent reduction in viability while PTEN-intact prostate cancer cells were unaffected, phenocopying genetic loss of CHD1. Overall, this study demonstrates the ligandability of the CHD1 chromodomains and suggests more potent and selective antagonists could translate to compounds of therapeutic value in PTEN-deficient cancers.
Insights
Researchers discovered UNC10142, a novel small molecule antagonist targeting CHD1 chromodomains. This compound effectively reduces viability in PTEN-deficient prostate cancer cells, highlighting CHD1 as a therapeutic target.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- CHD1 (chromodomain-helicase DNA-binding protein) recognizes H3K4me2/3 modifications.
- CHD1 is a synthetic lethal target in PTEN-deficient cancers.
Purpose of the Study:
- To discover and characterize small molecule antagonists of CHD1.
- To evaluate the therapeutic potential of CHD1 inhibition in PTEN-deficient cancers.
Main Methods:
- Small molecule screening and characterization (IC50 determination).
- Cocrystallography to determine binding mode.
- Cell-based assays to assess target engagement and anti-cancer activity.
Main Results:
- Discovery of UNC10142, a first-in-class CHD1 chromodomain antagonist (IC50 = 1.7 ± 0.2 μM).
- UNC10142 demonstrated target engagement in cell lysates.
- UNC10142 selectively reduced viability in PTEN-deficient prostate cancer cells, mimicking genetic CHD1 loss.
Conclusions:
- The CHD1 chromodomains are druggable targets.
- UNC10142 validates CHD1 as a therapeutic target in PTEN-deficient cancers.
- Development of more potent CHD1 antagonists holds promise for cancer therapy.
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