Reference Detail

Ref Type

Journal Article

PMID

(31000582)

Authors

Bevill SM, Olivares-Quintero JF, Sciaky N, Golitz BT, Singh D, Beltran AS, Rashid NU, Stuhlmiller TJ, Hale A, Moorman NJ, Santos CM, Angus SP, Zawistowski JS, Johnson GL

Title

GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	17	7	2019 07	1503-1518	Mol Cancer Res

URL

Abstract Text

Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast cancer (TNBC). GSK2801, an inhibitor of BAZ2A/B BDs, of the imitation switch chromatin remodeling complexes, and BRD9, of the SWI/SNF complex, demonstrated synergy independent of BRD4 control of P-TEFb-mediated pause-release of RNA polymerase II. GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. Additional displacement of BRD2 from rDNA in the nucleolus coincided with decreased 45S rRNA, revealing a function of BRD2 in regulating RNA polymerase I transcription. In 2D cultures, enhanced displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induced cleaved caspase-3 and cleaved PARP characteristic of apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC. IMPLICATIONS: Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BAZ2-ICR	BAZ2-ICR	0	0
BI-9564	BI-9564	0	0
CPI-637	CPI-637	0	0
GSK2801	GSK2801	0	0
HY-16462	HY-16462	0	0

Drug Name	Synonyms	Drug Classes	Drug Description
BAZ2-ICR			BAZ2-ICR is a selective BAZ2A and BAZ2B bromodomain inhibitor, which has potential antitumor activity (PMID: 25719566, PMID: 31000582).
BI-9564	BI9564\|BI 9564		BI-9564 is a selective BRD9 inhibitor that also has activity against BRD7 and CECR2, which has potential antitumor activity (PMID: 31000582, PMID: 26749027, PMID: 26914985).
CPI-637	CPI637\|CPI 637	CBP/p300 inhibitor 11	CPI-637 is a CBP/p300 bromodomain inhibitor, which may have antitumor activity (PMID: 27190605, PMID: 31000582).
GSK2801	GSK 2801\|GSK-2801		GSK2801 is a bromodomain inhibitor that selectively inhibits BAZ2A/B and BRD9, which has potential antitumor activity (PMID: 31000582).
HY-16462	HY16462\|HY 16462	CDK9 Inhibitor 21	HY-16462 is a CDK9 inhibitor, which has potential antitumor activity (PMID: 31000582).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References