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首页> 外文期刊>Nature >The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K
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The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

机译：CDK抑制剂CR8用作分子胶水降解剂，其耗尽细胞周期蛋白K.

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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.
机译：通过诱导CDK12-基蛋白K和DDB1之间的形成复合物的细胞周期蛋白依赖性激酶抑制剂CR8作用为分子胶化合物，这导致细胞周数K.molacular胶化合物诱导蛋白质 - 蛋白质相互作用的泛素化和降解遍霉素连接酶的背景下，导致蛋白质降解（1）。与传统的酶抑制剂不同，这些分子胶降解剂应算法以催化先前难以接近的靶标的快速耗尽（2）。它们在临床上有效和高度追捧，但迄今为止仅被偶然发现了。在这里，通过系统地采矿数据库进行4,518个临床和临床前小分子的细胞毒性与数百人癌细胞系（3-5）的E3连接酶组分的表达水平之间的相关性，我们鉴定CR8-A Cyclin依赖性激酶（CDK ）抑制剂（6） - 用作分子胶水降解剂的化合物。 CR8的CDK键合形式具有溶剂暴露的吡啶基部分，其诱导CDK12-基蛋白K和CUL4适配器蛋白DDB1之间的复合物的形成，绕过基底受体并呈现细胞周期蛋白K的普蛋白蛋白K.我们的研究表明，表面暴露的部分的化学改变可以赋予抑制剂的功能增益胶水性能，并且我们将其提出作为更广泛的策略，通过该策略，可以将靶结合分子转化为分子胶水。

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  • 来源
    《Nature》 |2020年第7824期|293-297|共5页
  • 作者

    Slabicki Mikolaj; Kozicka Zuzanna; Petzold Georg; Li Yen-Der; Manojkumar Manisha; Bunker Richard D.; Donovan Katherine A.; Sievers Quinlan L.; Koeppel Jonas; Suchyta Dakota; Sperling Adam S.; Fink Emma C.; Gasser Jessica A.; Wang Li R.; Corsello Steven M.; Sellar Rob S.; Jan Max; Gillingham Dennis; Scholl Claudia; Frohling Stefan; Golub Todd R.; Fischer Eric S.; Thoma Nicolas H.; Ebert Benjamin L.;

  • 作者单位

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|German Canc Res Ctr Div Translat Med Oncol Heidelberg Germany|Natl Ctr Tumor Dis NCT Heidelberg Germany;

    Friedrich Miescher Inst Biomed Res Basel Switzerland|Univ Basel Fac Sci Basel Switzerland;

    Friedrich Miescher Inst Biomed Res Basel Switzerland;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|Harvard Univ Dept Mol & Cellular Biol Cambridge MA 02138 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|German Canc Res Ctr Div Translat Med Oncol Heidelberg Germany|Natl Ctr Tumor Dis NCT Heidelberg Germany;

    Friedrich Miescher Inst Biomed Res Basel Switzerland|Monte Rosa Therapeut Basel Switzerland;

    Harvard Med Sch Dept Biol Chem & Mol Pharmacol Boston MA 02115 USA|Dana Farber Canc Inst Dept Canc Biol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|German Canc Res Ctr Div Translat Med Oncol Heidelberg Germany|Natl Ctr Tumor Dis NCT Heidelberg Germany;

    Friedrich Miescher Inst Biomed Res Basel Switzerland|Univ Basel Fac Sci Basel Switzerland;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|UCL UCL Canc Inst Dept Haematol London England;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA;

    Univ Basel Fac Sci Basel Switzerland;

    Natl Ctr Tumor Dis NCT Heidelberg Germany|German Canc Res Ctr Div Appl Funct Genom Heidelberg Germany;

    German Canc Res Ctr Div Translat Med Oncol Heidelberg Germany|Natl Ctr Tumor Dis NCT Heidelberg Germany|German Canc Consortium Heidelberg Germany;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Pediat Oncol Boston MA 02115 USA|Howard Hughes Med Inst Boston MA 02115 USA;

    Harvard Univ Dept Mol & Cellular Biol Cambridge MA 02138 USA|Harvard Med Sch Dept Biol Chem & Mol Pharmacol Boston MA 02115 USA;

    Friedrich Miescher Inst Biomed Res Basel Switzerland;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA|Howard Hughes Med Inst Boston MA 02115 USA;

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