2. Academic Validation
  3. Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors

Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors

  • J Med Chem. 2023 Dec 28;66(24):16783-16806. doi: 10.1021/acs.jmedchem.3c01529.
Kevin B Teuscher,  Jonathan J Mills,  Jianhua Tian 1,  Changho Han,  Kenneth M Meyers,  Jiqing Sai,  Taylor M South,  Mackenzie M Crow,  Mayme Van Meveren,  John L Sensintaffar,  Bin Zhao,  Kangsa Amporndanai,  William J Moore 2,  Gordon M Stott 3,  William P Tansey,  Taekyu Lee,  Stephen W Fesik 4
Affiliations

Affiliations

  • 1 Molecular Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Nashville, Tennessee 37232-0142, United States.
  • 2 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702-1201, United States.
  • 3 Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701-4907, United States.
  • 4 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232-0142, United States.
PMID: 38085679 DOI: 10.1021/acs.jmedchem.3c01529
Abstract

The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural analysis to design partially saturated bicyclic P7 units. These benzoxazepinone-based inhibitors exhibited increased cellular potency and selectivity and favorable physicochemical properties compared to our best-in-class dihydroisoquinolinone-based counterparts. This study opens avenues to discover more advanced WDR5 WIN-site inhibitors and supports their development as novel anti-cancer therapeutics.

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