Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1

被引：59

作者：

Hansen, Joshua D. ^{[1
]}

Condroski, Kevin ^{[1
]}

Correa, Matthew ^{[1
]}

Muller, George ^{[1
]}

Man, Hon-Wah ^{[1
]}

Ruchelman, Alexander ^{[1
]}

Zhang, Weihong ^{[1
]}

Vocanson, Fan ^{[1
]}

Crea, Tim ^{[1
]}

Liu, Wei ^{[1
]}

Lu, Gang ^{[1
]}

Baculi, Frans ^{[1
]}

LeBrun, Laurie ^{[1
]}

Mahmoudi, Afshin ^{[1
]}

Carmel, Gilles ^{[1
]}

Hickman, Matt ^{[1
]}

Lu, Chin-Chun ^{[1
]}

机构：

[1] Celgene Corp, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 02期

关键词：

CEREBLON; TARGET; TRANSLATION; TERMINATION;

D O I：

10.1021/acs.jmedchem.6b01911

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAP. that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.

引用

页码：492 / 503

页数：12

共 24 条

[1]

[Anonymous], 2016, STARDROP VERS 6 2

[2] Random forests [J].

Breiman, L .

MACHINE LEARNING, 2001, 45 (01) :5-32

[3] Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs [J].

Chamberlain, Philip P. ;

Lopez-Girona, Antonia ;

Miller, Karen ;

Carmel, Gilles ;

Pagarigan, Barbra ;

Chie-Leon, Barbara ;

Rychak, Emily ;

Corral, Laura G. ;

Ren, Yan J. ;

Wang, Maria ;

Riley, Mariko ;

Delker, Silvia L. ;

Ito, Takumi ;

Ando, Hideki ;

Mori, Tomoyuki ;

Hirano, Yoshinori ;

Handa, Hiroshi ;

Hakoshima, Toshio ;

Daniel, Thomas O. ;

Cathers, Brian E. .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2014, 21 (09) :803-809

[4] Structural insights into eRF3 and stop codon recognition by eRF1 [J].

Cheng, Zhihong ;

Saito, Kazuki ;

Pisarev, Andrey V. ;

Wada, Miki ;

Pisareva, Vera P. ;

Pestova, Tatyana V. ;

Gajda, Michal ;

Round, Adam ;

Kong, Chunguang ;

Lim, Mengkiat ;

Nakamura, Yoshikazu ;

Svergun, Dmitri I. ;

Ito, Koichi ;

Song, Haiwei .

GENES & DEVELOPMENT, 2009, 23 (09) :1106-1118

[5] The JAZ family of repressors is the missing link in jasmonate signalling [J].

Chini, Andrea ;

Fonseca, S. ;

Fernandez, G. ;

Adie, B. ;

Chico, J. M. ;

Lorenzo, O. ;

Garcia-Casado, G. ;

Lopez-Vidriero, I. ;

Lozano, F. M. ;

Ponce, M. R. ;

Micol, J. L. ;

Solano, R. .

NATURE, 2007, 448 (7154) :666-+

[6] Prime time for PROTACs [J].

Deshaies, Raymond J. .

NATURE CHEMICAL BIOLOGY, 2015, 11 (09) :634-635

[7] Identification of a Primary Target of Thalidomide Teratogenicity [J].

Ito, Takumi ;

Ando, Hideki ;

Suzuki, Takayuki ;

Ogura, Toshihiko ;

Hotta, Kentaro ;

Imamura, Yoshimasa ;

Yamaguchi, Yuki ;

Handa, Hiroshi .

SCIENCE, 2010, 327 (5971) :1345-1350

[8] Lenalidomide induces ubiquitination and degradation of CK1a in del(5q) MDS [J].

Kroenke, Jan ;

Fink, Emma C. ;

Hollenbach, Paul W. ;

MacBeth, Kyle J. ;

Hurst, Slater N. ;

Udeshi, Namrata D. ;

Chamberlain, Philip P. ;

Mani, D. R. ;

Man, Hon Wah ;

Gandhi, Anita K. ;

Svinkina, Tanya ;

Schneider, Rebekka K. ;

McConkey, Marie ;

Jaeras, Marcus ;

Griffiths, Elizabeth ;

Wetzler, Meir ;

Bullinger, Lars ;

Cathers, Brian E. ;

Carr, Steven A. ;

Chopra, Rajesh ;

Ebert, Benjamin L. .

NATURE, 2015, 523 (7559) :183-U102

[9] Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells [J].

Kroenke, Jan ;

Udeshi, Namrata D. ;

Narla, Anupama ;

Grauman, Peter ;

Hurst, Slater N. ;

McConkey, Marie ;

Svinkina, Tanya ;

Heckl, Dirk ;

Comer, Eamon ;

Li, Xiaoyu ;

Ciarlo, Christie ;

Hartman, Emily ;

Munshi, Nikhil ;

Schenone, Monica ;

Schreiber, Stuart L. ;

Carr, Steven A. ;

Ebert, Benjamin L. .

SCIENCE, 2014, 343 (6168) :301-305

[10] The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins [J].

Lu, Gang ;

Middleton, Richard E. ;

Sun, Huahang ;

Naniong, MarkVic ;

Ott, Christopher J. ;

Mitsiades, Constantine S. ;

Wong, Kwok-Kin ;

Bradner, James E. ;

Kaelin, William G., Jr. .

SCIENCE, 2014, 343 (6168) :305-309

← 1 2 3 →