2. Academic Validation
  3. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

  • J Med Chem. 2017 Jun 22;60(12):4805-4817. doi: 10.1021/acs.jmedchem.6b01336.
Alex M Ayoub 1,  Laura M L Hawk 1,  Ryan J Herzig 2,  Jiewei Jiang 2,  Andrea J Wisniewski 2,  Clifford T Gee 1,  Peiliang Zhao 2,  Jin-Yi Zhu 3,  Norbert Berndt 3,  Nana K Offei-Addo 4,  Thomas G Scott 4,  Jun Qi 4,  James E Bradner 4,  Timothy R Ward 2,  Ernst Schönbrunn 3,  Gunda I Georg 2,  William C K Pomerantz 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
  • 3 Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, Florida 33612, United States.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, 360 Longwood Avenue, Boston, Massachusetts 02215, United States.
PMID: 28535045 DOI: 10.1021/acs.jmedchem.6b01336
Abstract

Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, Cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

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