Targeting transcription in heart failure via CDK7/12/13 inhibition

Austin Hsu, Qiming Duan, Daniel S. Day, Xin Luo, Sarah McMahon, Yu Huang, Zachary B. Feldman, Zhen Jiang, Tinghu Zhang, Yanke Liang, Michael Alexanian, Arun Padmanabhan, Jonathan D. Brown, Charles Y. Lin, Nathanael S. Gray, Richard A. Young, Benoit G. Bruneau () and Saptarsi M. Haldar ()
Additional contact information
Austin Hsu: Gladstone Institutes
Qiming Duan: Gladstone Institutes
Daniel S. Day: Whitehead Institute for Biomedical Research
Xin Luo: Amgen Research
Sarah McMahon: Gladstone Institutes
Yu Huang: Gladstone Institutes
Zachary B. Feldman: Vanderbilt University Medical Center
Zhen Jiang: Gladstone Institutes
Tinghu Zhang: Dana-Farber Cancer Institute
Yanke Liang: Harvard Medical School
Michael Alexanian: Gladstone Institutes
Arun Padmanabhan: Gladstone Institutes
Jonathan D. Brown: Vanderbilt University Medical Center
Charles Y. Lin: Baylor College of Medicine
Nathanael S. Gray: Dana-Farber Cancer Institute
Richard A. Young: Whitehead Institute for Biomedical Research
Benoit G. Bruneau: Gladstone Institutes
Saptarsi M. Haldar: Gladstone Institutes

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Heart failure with reduced ejection fraction (HFrEF) is associated with high mortality, highlighting an urgent need for new therapeutic strategies. As stress-activated cardiac signaling cascades converge on the nucleus to drive maladaptive gene programs, interdicting pathological transcription is a conceptually attractive approach for HFrEF therapy. Here, we demonstrate that CDK7/12/13 are critical regulators of transcription activation in the heart that can be pharmacologically inhibited to improve HFrEF. CDK7/12/13 inhibition using the first-in-class inhibitor THZ1 or RNAi blocks stress-induced transcription and pathologic hypertrophy in cultured rodent cardiomyocytes. THZ1 potently attenuates adverse cardiac remodeling and HFrEF pathogenesis in mice and blocks cardinal features of disease in human iPSC-derived cardiomyocytes. THZ1 suppresses Pol II enrichment at stress-transactivated cardiac genes and inhibits a specific pathologic gene program in the failing mouse heart. These data identify CDK7/12/13 as druggable regulators of cardiac gene transactivation during disease-related stress, suggesting that HFrEF features a critical dependency on transcription that can be therapeutically exploited.

Date: 2022
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DOI: 10.1038/s41467-022-31541-8

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