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

Journal Article · · J. Med. Chem.

Research Organization:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
DOE - Office Of Science; INDUSTRY
OSTI ID:
1900949
Journal Information:
J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (17) Vol. 65
Country of Publication:
United States
Language:
ENGLISH

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The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326) journal January 2016
Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target journal December 2019
Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo journal November 2015
Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring journal July 2014
Discovery of (2 S )-8-[(3 R )-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2 H -pyrimido[1,2- a ]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors journal July 2014
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Genetic effects on gene expression across human tissues journal October 2017
Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo journal October 2014
Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles journal May 2017
Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism journal November 2017
Functional genomic landscape of cancer-intrinsic evasion of killing by T cells journal September 2020
The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34 journal July 2016
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Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function journal January 2012
Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner journal October 2017
Autophagy-monitoring and autophagy-deficient mice journal September 2017
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Overview of the CCP 4 suite and current developments journal March 2011
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Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti–PD-1/PD-L1 immunotherapy journal May 2020
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Autophagy protects tumors from T cell–mediated cytotoxicity via inhibition of TNFα-induced apoptosis journal December 2020
Mechanisms of Autophagy Initiation journal June 2017
Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells journal March 2013
VPS34 complexes from a structural perspective journal February 2019
Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase activating protein Armus journal January 2016
A Novel Method for High Throughput Lipophilicity Determination by Microscale Shake Flask and Liquid Chromatography Tandem Mass Spectrometry journal November 2013

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