title: SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.
abstract: Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: mike.curtin@abbvie.com.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Curtin
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Pliushchev
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Huan-Qiu
authors.initials: HQ
authors.lastname: Li
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Dietrich
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Haizhong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Ji
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Clark
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Sarris
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Selvaraju
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Bailin
authors.initials: B
authors.lastname: Shaw
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Mikkel A
authors.initials: MA
authors.lastname: Algire
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: He
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Richardson
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Ramzi F
authors.initials: RF
authors.lastname: Sweis
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chiang
authors.affiliation: AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000621531:1-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-4-(4-(4-(methanesulfonyl)piperazin-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine; D000970:Antineoplastic Agents; C491488:EED protein, human; D008024:Ligands; D011759:Pyrrolidines; D013449:Sulfonamides; D063151:Polycomb Repressive Complex 2
keywords: Cancer; EED; PRC2; Protein-protein interaction inhibitor (PPI)