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Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo.

ABSTRACT: Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34, which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models.

SUBMITTER: Honda A

PROVIDER: S-EPMC4716600 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo.

Honda Ayako A Harrington Edmund E Cornella-Taracido Ivan I Furet Pascal P Knapp Mark S MS Glick Meir M Triantafellow Ellen E Dowdle William E WE Wiedershain Dmitri D Maniara Wieslawa W Moore Christine C Finan Peter M PM Hamann Lawrence G LG Firestone Brant B Murphy Leon O LO Keaney Erin P EP

ACS medicinal chemistry letters 20151113 1

Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34, which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models. ...[more]

PMID: 26819669

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