Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma
ELIFE
Authors: Brien, Gerard L.; Remillard, David; Shi, Junwei; Hemming, Matthew L.; Chabon, Jonathon; Wynne, Kieran; Dillon, Eugene T.; Cagney, Gerard; Van Mierlo, Guido; Baltissen, Marijke P.; Vermeulen, Michiel; Qi, Jun; Froehling, Stefan; Gray, Nathanael S.; Bradner, James E.; Vakoc, Christopher R.; Armstrong, Scott A.
Abstract
Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.
Discovery of Pyrrolo[3,2-d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain
JOURNAL OF MEDICINAL CHEMISTRY
Authors: Huang, Luyi; Li, Hui; Li, Linli; Niu, Lu; Seupel, Raina; Wu, Chengyong; Cheng, Wei; Chen, Chong; Ding, Bisen; Brennan, Paul E.; Yang, Shengyong
Abstract
Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, (R,R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a K-D of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.
COA
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