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

被引：45

作者：

Honda, Ayako ^{[1
]}

Harrington, Edmund ^{[1
]}

Cornella-Taracido, Ivan ^{[1
]}

Furet, Pascal ^{[3
]}

Knapp, Mark S. ^{[2
]}

Glick, Meir ^{[1
]}

Triantafellow, Ellen ^{[1
]}

Dowdle, William E. ^{[1
]}

Wiedershain, Dmitri ^{[1
]}

Maniara, Wieslawa ^{[1
]}

Moore, Christine ^{[1
]}

Finan, Peter M. ^{[1
]}

Hamann, Lawrence G. ^{[1
]}

Firestone, Brant ^{[1
]}

Murphy, Leon O. ^{[1
]}

Keaney, Erin P. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Novartis Inst BioMed Res, 4560 Horton St, Emeryville, CA 94608 USA

[3] Novartis Inst BioMed Res, Novartis Campus, CH-4056 Basel, Switzerland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 01期

关键词：

VPS34; autophagy; phosphoinositide; 3-kinase;

D O I：

10.1021/acsmedchemlett.5b00335

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：72 / 76

页数：5

共 15 条

[1] Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum [J].

Axe, Elizabeth L. ;

Walker, Simon A. ;

Manifava, Maria ;

Chandra, Priya ;

Roderick, H. Llewelyn ;

Habermann, Anja ;

Griffiths, Gareth ;

Ktistakis, Nicholas T. .

JOURNAL OF CELL BIOLOGY, 2008, 182 (04) :685-701

[2] Emerging regulation and functions of autophagy [J].

Boya, Patricia ;

Reggiori, Fulvio ;

Codogno, Patrice .

NATURE CELL BIOLOGY, 2013, 15 (07) :713-720

[3]

Choi AMK, 2013, NEW ENGL J MED, V368, P1845, DOI [10.1056/NEJMra1205406, 10.1056/NEJMc1303158]

[4]

Cornella-Taracido I., 2012, Bi-heteroaryl compounds as vps34 inhibitors, Patent No. [WO2012085815, 2012085815]

[5] Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo [J].

Dowdle, William E. ;

Nyfeler, Beat ;

Nagel, Jane ;

Elling, Robert A. ;

Liu, Shanming ;

Triantafellow, Ellen ;

Menon, Suchithra ;

Wang, Zuncai ;

Honda, Ayako ;

Pardee, Gwynn ;

Cantwell, John ;

Luu, Catherine ;

Cornella-Taracido, Ivan ;

Harrington, Edmund ;

Fekkes, Peter ;

Lei, Hong ;

Fang, Qing ;

Digan, Mary Ellen ;

Burdick, Debra ;

Powers, Andrew F. ;

Helliwell, Stephen B. ;

D'Aquin, Simon ;

Bastien, Julie ;

Wang, Henry ;

Wiederschain, Dmitri ;

Kuerth, Jenny ;

Bergman, Philip ;

Schwalb, David ;

Thomas, Jason ;

Ugwonali, Savuth ;

Harbinski, Fred ;

Tallarico, John ;

Wilson, Christopher J. ;

Myer, Vic E. ;

Porter, Jeffery A. ;

Bussiere, Dirksen E. ;

Finan, Peter M. ;

Labow, Mark A. ;

Mao, Xiaohong ;

Hamann, Lawrence G. ;

Manning, Brendan D. ;

Valdez, Reginald A. ;

Nicholson, Thomas ;

Schirle, Markus ;

Knapp, Mark S. ;

Keaney, Erin P. ;

Murphy, Leon O. .

NATURE CELL BIOLOGY, 2014, 16 (11) :1069-+

[6] PI3K and cancer: lessons, challenges and opportunities [J].

Fruman, David A. ;

Rommel, Christian .

NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (02) :140-156

[7] To Be or Not to Be? How Selective Autophagy and Cell Death Govern Cell Fate [J].

Green, Douglas R. ;

Levine, Beth .

CELL, 2014, 157 (01) :65-75

[8]

Maira SM, 2008, EXPERT OPIN THER TAR, V12, P223, DOI [10.1517/14728222.12.2.223, 10.1517/14728222.12.2.223 ]

[9] Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L [J].

Matsunaga, Kohichi ;

Morita, Eiji ;

Saitoh, Tatsuya ;

Akira, Shizuo ;

Ktistakis, Nicholas T. ;

Izumi, Tetsuro ;

Noda, Takeshi ;

Yoshimori, Tamotsu .

JOURNAL OF CELL BIOLOGY, 2010, 190 (04) :511-521

[10] Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34 [J].

Miller, Simon ;

Tavshanjian, Brandon ;

Oleksy, Arkadiusz ;

Perisic, Olga ;

Houseman, Benjamin T. ;

Shokat, Kevan M. ;

Williams, Roger L. .

SCIENCE, 2010, 327 (5973) :1638-1642

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