The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

被引：295

作者：

Slabicki, Mikolaj ^{[1
,2
,3
,4
]}

Kozicka, Zuzanna ^{[5
,6
]}

Petzold, Georg ^{[5
]}

Li, Yen-Der ^{[1
,2
,7
]}

Manojkumar, Manisha ^{[1
,2
,3
,4
]}

Bunker, Richard D. ^{[5
,15
]}

Donovan, Katherine A. ^{[8
,9
]}

Sievers, Quinlan L. ^{[1
,2
]}

Koeppel, Jonas ^{[1
,2
,3
,4
]}

Suchyta, Dakota ^{[5
,6
]}

Sperling, Adam S. ^{[1
,2
]}

Fink, Emma C. ^{[1
,2
]}

Gasser, Jessica A. ^{[1
,2
]}

Wang, Li R. ^{[1
]}

Corsello, Steven M. ^{[1
,2
]}

Sellar, Rob S. ^{[1
,2
,10
]}

Jan, Max ^{[1
,2
]}

Gillingham, Dennis ^{[6
]}

Scholl, Claudia ^{[4
,11
]}

Frohling, Stefan ^{[3
,4
,12
]}

Golub, Todd R. ^{[1
,13
,14
]}

Fischer, Eric S. ^{[7
,8
]}

Thoma, Nicolas H. ^{[5
]}

Ebert, Benjamin L. ^{[1
,2
,14
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] German Canc Res Ctr, Div Translat Med Oncol, Heidelberg, Germany

[4] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[5] Friedrich Miescher Inst Biomed Res, Basel, Switzerland

[6] Univ Basel, Fac Sci, Basel, Switzerland

[7] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA

[8] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[9] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[10] UCL, UCL Canc Inst, Dept Haematol, London, England

[11] German Canc Res Ctr, Div Appl Funct Genom, Heidelberg, Germany

[12] German Canc Consortium, Heidelberg, Germany

[13] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[14] Howard Hughes Med Inst, Boston, MA 02115 USA

[15] Monte Rosa Therapeut, Basel, Switzerland

来源：

NATURE | 2020年 / 585卷 / 7824期

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

UBIQUITIN LIGASE; SELECTIVE DEGRADATION; DEPENDENT KINASES; ROSCOVITINE; IDENTIFICATION; ARCHITECTURE; EXPRESSION; VECTORS; TARGET; POTENT;

D O I：

10.1038/s41586-020-2374-x

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：

The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12-cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K. Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation(1). Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets(2). They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines(3-5), we identify CR8-a cyclin-dependent kinase (CDK) inhibitor(6)-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.

引用

页码：293 / +

页数：26

共 51 条

[1] A set of baculovirus transfer vectors for screening of affinity tags and parallel expression strategies [J].