title: Protein Degradation via CRL4CRBNUbiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1.
abstract: 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.
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Joshua D
authors.identifier: 0000-0002-4881-5247
authors.initials: JD
authors.lastname: Hansen
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Condroski
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Correa
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: George
authors.initials: G
authors.lastname: Muller
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Hon-Wah
authors.initials: HW
authors.lastname: Man
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ruchelman
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Fan
authors.initials: F
authors.lastname: Vocanson
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Tim
authors.initials: T
authors.lastname: Crea
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Frans
authors.initials: F
authors.lastname: Baculi
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Laurie
authors.initials: L
authors.lastname: LeBrun
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Afshin
authors.initials: A
authors.lastname: Mahmoudi
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Gilles
authors.initials: G
authors.lastname: Carmel
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Matt
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Celgene Corporation , 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Chin-Chun
authors.initials: CC
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051740:Ikaros Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009101:Multiple Myeloma; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D010454:Peptide Termination Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010797:Phthalimides / Q000737:chemistry; D010881:Piperidones / Q000737:chemistry; D059748:Proteolysis / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D053722:Receptors, Interleukin-17
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051740:Ikaros Transcription Factor; D010447:Peptide Hydrolases; D010454:Peptide Termination Factors; D010797:Phthalimides; D010881:Piperidones; D044767:Ubiquitin-Protein Ligases; C502543:CRBN protein, human; C106285:IKZF3 protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C087971:peptide-chain-release factor 3; C037432:phthalimidine; C007864:glutarimide