2. Academic Validation
  3. Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance

  • Bioorg Med Chem Lett. 2017 Aug 1;27(15):3534-3541. doi: 10.1016/j.bmcl.2017.05.063.
Terry D Crawford 1,  Steffan Vartanian 2,  Alexandre Côté 3,  Steve Bellon 3,  Martin Duplessis 3,  E Megan Flynn 2,  Michael Hewitt 3,  Hon-Ren Huang 3,  James R Kiefer 2,  Jeremy Murray 2,  Christopher G Nasveschuk 3,  Eneida Pardo 3,  F Anthony Romero 2,  Peter Sandy 3,  Yong Tang 3,  Alexander M Taylor 3,  Vickie Tsui 2,  Jian Wang 4,  Shumei Wang 2,  Laura Zawadzke 3,  Brian K Albrecht 3,  Steven R Magnuson 2,  Andrea G Cochran 2,  David Stokoe 5
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: terrydc@gene.com.
  • 2 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3 Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, United States.
  • 4 Wuxi Apptec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
  • 5 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: dhstokoe@calicolabs.com.
PMID: 28606761 DOI: 10.1016/j.bmcl.2017.05.063
Abstract

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple Cancer cell lines. To assess the functional role of BRD9 in Cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance.

Keywords

BRD9; Bromodomain; Epigenetics; Inhibitor; Resistance.

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