2 research outputs found
Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors
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
Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors
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