2. Academic Validation
  3. Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

  • Cell. 2018 Nov 15;175(5):1244-1258.e26. doi: 10.1016/j.cell.2018.09.051.
Hanghang Zhang 1,  Somnath Pandey 1,  Meghan Travers 2,  Hongxing Sun 1,  George Morton 3,  Jozef Madzo 1,  Woonbok Chung 1,  Jittasak Khowsathit 4,  Oscar Perez-Leal 5,  Carlos A Barrero 5,  Carmen Merali 5,  Yasuyuki Okamoto 1,  Takahiro Sato 1,  Joshua Pan 6,  Judit Garriga 1,  Natarajan V Bhanu 7,  Johayra Simithy 7,  Bela Patel 1,  Jian Huang 1,  Noël J-M Raynal 8,  Benjamin A Garcia 7,  Marlene A Jacobson 3,  Cigall Kadoch 6,  Salim Merali 5,  Yi Zhang 1,  Wayne Childers 3,  Magid Abou-Gharbia 3,  John Karanicolas 9,  Stephen B Baylin 2,  Cynthia A Zahnow 2,  Jaroslav Jelinek 1,  Xavier Graña 1,  Jean-Pierre J Issa 10
Affiliations

Affiliations

  • 1 Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
  • 2 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
  • 3 Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • 4 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
  • 5 Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
  • 6 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • 7 Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Département de pharmacologie et physiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada.
  • 9 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 10 Fels Institute for Cancer Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address: [email protected].
PMID: 30454645 DOI: 10.1016/j.cell.2018.09.051
Abstract

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in Cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 Inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo Cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of Cancer.

Keywords

BRG1; CDK9; DNA methylation; SMARCA4; SWI/SNF; drug development; epigenetic therapy; gene silencing; immunosensitization; kinase inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-119940
    98.41%, CDK9-Cyclin T1 Inhibitor
    CDK