Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor

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Laetitia J Martin1, Manfred Koegl1, Gerd Bader1

  • 1Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.

Journal of Medicinal Chemistry
|February 26, 2016
PubMed

Insights

Researchers developed novel inhibitors targeting the BRD9 bromodomain within the SWI/SNF complex. These compounds show antitumor activity, offering new tools to study BRD9

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Mutations in the SWI/SNF complex are linked to cancer.
  • The specific roles of individual SWI/SNF subunits, like BRD9, in oncogenesis are not fully understood.

Purpose of the Study:

  • To develop a potent and selective inhibitor for the BRD9 bromodomain.
  • To evaluate the function of BRD9 within the SWI/SNF complex and its role in cancer.

Main Methods:

  • Discovery and development of a novel pyridinone-like scaffold targeting the BRD9 bromodomain.
  • Utilizing crystallographic data to optimize inhibitor potency and selectivity against BRD4.
  • Assessing cellular function modulation and in vivo antitumor activity in an AML xenograft model.

Main Results:

  • Identification of a potent and selective BRD9 bromodomain inhibitor series.
  • Demonstration of BRD9 inhibition modulating cellular function.
  • Exhibition of significant antitumor activity in an acute myeloid leukemia (AML) xenograft model.

Conclusions:

  • Novel chemical probes (BI-7273 and BI-9564) targeting BRD9 have been developed.
  • These probes are valuable tools for further in vitro and in vivo investigation of BRD9 biology.
  • Targeting BRD9 offers a potential therapeutic strategy for cancers with SWI/SNF mutations.

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