Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

被引：90

作者：

Bohnacker, Thomas ^{[1
]}

Prota, Andrea E. ^{[2
]}

Beaufils, Florent ^{[1
,7
]}

Burke, John E. ^{[3
]}

Melone, Anna ^{[1
]}

Inglis, Alison J. ^{[4
]}

Rageot, Denise ^{[1
]}

Sele, Alexander M. ^{[1
]}

Cmiljanovic, Vladimir ^{[1
,7
]}

Cmiljanovic, Natasa ^{[1
,7
]}

Bargsten, Katja ^{[2
,9
]}

Aher, Amol ^{[5
]}

Akhmanova, Anna ^{[5
]}

Fernando Diaz, J. ^{[6
]}

Fabbro, Doriano ^{[7
]}

Zvelebil, Marketa ^{[8
]}

Williams, Roger L. ^{[4
]}

Steinmetz, Michel O. ^{[2
]}

Wymann, Matthias P. ^{[1
]}

机构：

[1] Univ Basel, Dept Biomed, CH-4058 Basel, Switzerland

[2] Paul Scherrer Inst, Dept Biol & Chem, Lab Biomol Res, CH-5232 Villigen, Switzerland

[3] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 2Y2, Canada

[4] MRC Lab Mol Biol, Cambridge CB2 2QH, England

[5] Univ Utrecht, Cell Biol, Fac Sci, NL-3584 CH Utrecht, Netherlands

[6] CIB Ctr Invest Biol, Madrid 28040, Spain

[7] PIQUR Therapeut AG, CH-4057 Basel, Switzerland

[8] Inst Canc Res, London SW3 6JB, England

[9] Univ Zurich, Inst Biochem, CH-8057 Zurich, Switzerland

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

瑞士国家科学基金会;

关键词：

METASTATIC BREAST-CANCER; ADVANCED SOLID TUMORS; IN-VITRO; PI3-KINASE INHIBITOR; KINASE INHIBITOR; DOSE-ESCALATION; CELL-DEATH; PHASE-I; NVP-BKM120; BKM120;

D O I：

10.1038/ncomms14683

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.

引用

页数：13

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