Details

Autor(en) / Beteiligte

• Hu, Dennis X.
• Patel, Snahel
• Chen, Huifen
• Wang, Shumei
• Staben, Steven T.
• Dimitrova, Yoana N.
• Wallweber, Heidi Ackerly
• Lee, Joanna Y.
• Chan, Grace Ka Yan
• Sneeringer, Christopher J.
• Prangley, Madeleine S.
• Moffat, John G.
• Wu, Kai C.
• Schutt, Leah K.
• Salphati, Laurent
• Pang, Jodie
• McNamara, Erin
• Huang, Haochu
• Chen, Yong
• Wang, Yunli
• Zhao, Wensheng
• Lim, Junghyun
• Murthy, Aditya
• Siu, Michael

Titel

Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2022-09, Vol.65 (17), p.11500-11512

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure–activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.