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

  • ACS Med Chem Lett. 2015 Nov 13;7(1):72-6. doi: 10.1021/acsmedchemlett.5b00335.
Ayako Honda  1 ,  Edmund Harrington  1 ,  Ivan Cornella-Taracido  1 ,  Pascal Furet  2 ,  Mark S Knapp  3 ,  Meir Glick  1 ,  Ellen Triantafellow  1 ,  William E Dowdle  1 ,  Dmitri Wiedershain  1 ,  Wieslawa Maniara  1 ,  Christine Moore  1 ,  Peter M Finan  1 ,  Lawrence G Hamann  1 ,  Brant Firestone  1 ,  Leon O Murphy  1 ,  Erin P Keaney  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 2. Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
  • 3. Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
PMID: 26819669 DOI: 10.1021/acsmedchemlett.5b00335
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.

Keywords
VPS34; autophagy; phosphoinositide 3-kinase.
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