Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.
Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.
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DOI：
10.1038/s41467-024-44698-1
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发表时间：
2024-01-16
影响因子：
16.6
通讯作者：
Rankovic, Zoran
中科院分区：
文献类型：
--
作者：
Nishiguchi, Gisele;Mascibroda, Lauren G.;Young, Sarah M.;Caine, Elizabeth A.;Abdelhamed, Sherif;Kooijman, Jeffrey J.;Miller, Darcie J.;Das, Sourav;McGowan, Kevin;Mayasundari, Anand;Shi, Zhe;Barajas, Juan M.;Hiltenbrand, Ryan;Aggarwal, Anup;Chang, Yunchao;Mishra, Vibhor;Narina, Shilpa;Thomas, Melvin;Loughran, Allister J.;Kalathur, Ravi;Yu, Kaiwen;Zhou, Suiping;Wang, Xusheng;High, Anthony A.;Peng, Junmin;Pruett-Miller, Shondra M.;Daniels, Danette L.;Urh, Marjeta;Shelat, Anang A.;Mullighan, Charles G.;Riching, Kristin M.;Zaman, Guido J. R.;Fischer, Marcus;Klco, Jeffery M.;Rankovic, Zoran
分子胶降解剂是诱导E3连接酶和靶蛋白之间特异性相互作用的小分子，导致靶蛋白水解。分子胶降解剂的发现目前主要依赖于筛选方法。在这里，我们描述了针对一组患者来源的癌细胞系筛选cereblon（CRBN）配体库，从而发现了SJ 7095，一种CK 1 α、IKZF 1和IKZF 3蛋白的强效降解剂。通过对这种小分子的结构活性关系（SAR）进行结构探索，我们开发了SJ 3149，这是一种体外和体内CK 1 α蛋白的选择性且有效的降解剂。SJ 3149与CK 1 α + CRBN + DDB 1复合共结晶的结构为该化合物的降解性能改善提供了依据。在一组115个癌细胞系中，SJ 3149显示出广泛的抗增殖活性特征，这与MDM 2抑制剂Nutlin-3a显示出统计学显着相关性。这些发现表明选择性CK 1 α降解剂在治疗血液系统癌症和实体瘤中具有潜在的效用。在这里，作者描述了一种有效的和选择性的CK 1a分子胶降解剂，具有广泛的抗增殖潜力。晶体学数据为该化合物显示的高降解效力提供了依据。
Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors. Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.
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影响因子：
7.3
作者：
Bowman BM;Sebolt KA;Hoff BA;Boes JL;Daniels DL;Heist KA;Galbán CJ;Patel RM;Zhang J;Beer DG;Ross BD;Rehemtulla A;Galbán S
通讯作者：
Galbán S
影响因子：
4
作者：
Ebert BL
通讯作者：
Ebert BL
影响因子：
7.3
作者：
Hansen, Joshua D.;Condroski, Kevin;Lu, Chin-Chun
通讯作者：
Lu, Chin-Chun
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi
DOI：
10.1158/1078-0432.ccr-13-2281
发表时间：
2014-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bandopadhayay P;Bergthold G;Nguyen B;Schubert S;Gholamin S;Tang Y;Bolin S;Schumacher SE;Zeid R;Masoud S;Yu F;Vue N;Gibson WJ;Paolella BR;Mitra SS;Cheshier SH;Qi J;Liu KW;Wechsler-Reya R;Weiss WA;Swartling FJ;Kieran MW;Bradner JE;Beroukhim R;Cho YJ
通讯作者：
Cho YJ