3 years ago

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

Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure–Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1
Alexander Ruchelman, Tim Crea, George Muller, Gilles Carmel, Weihong Zhang, Joshua D. Hansen, Matt Hickman, Chin-Chun Lu, Fan Vocanson, Hon-Wah Man, Kevin Condroski, Afshin Mahmoudi, Laurie LeBrun, Wei Liu, Matthew Correa, Frans Baculi, Gang Lu
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 SAR 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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.6b01911

DOI: 10.1021/acs.jmedchem.6b01911

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