SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Bioorganic and Medicinal Chemistry Letters

Volumn 27, Issue 7, 2017, Pages 1576-1583

  Curtin, Michael L ^a   Pliushchev, Marina A ^a   Li, Huan Qiu ^a   Torrent, Maricel ^a   Dietrich, Justin D ^a   Jakob, Clarissa G ^a   Zhu, Haizhong ^a   Zhao, Hongyu ^a   Wang, Ying ^a   Ji, Zhiqin ^a   Clark, Richard F ^a   Sarris, Kathy A ^a   Selvaraju, Sujatha ^a   Shaw, Bailin ^a   Algire, Mikkel A ^a   He, Yupeng ^a   Richardson, Paul L ^a   Sweis, Ramzi F ^a   Sun, Chaohong ^a   Chiang, Gary G ^a   Michaelides, Michael R ^a   more..

^a ABBVIE INC   (United States)

Author keywords

Cancer; EED; PRC2; Protein protein interaction inhibitor (PPI)

Indexed keywords

ANTINEOPLASTIC AGENT; EMBRYONIC ECTODERM DEVELOPMENT PROTEIN; HYDROGEN; POLYCOMB REPRESSIVE COMPLEX 2; PYRROLIDINE DERIVATIVE; 1-(7-FLUORO-2,3-DIHYDRO-1H-INDEN-1-YL)-4-(4-(4-(METHANESULFONYL)PIPERAZIN-1-YL)PHENYL)-N,N-DIMETHYLPYRROLIDIN-3-AMINE; EED PROTEIN, HUMAN; LIGAND; PROTEIN BINDING; SULFONAMIDE;

ALLOSTERISM; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; ARTIFICIAL MEMBRANE; B-CELL LYMPHOMA CELL LINE; CANCER INHIBITION; CHIRAL CHROMATOGRAPHY; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIFFUSE LARGE B CELL LYMPHOMA; DRUG BINDING SITE; DRUG CLEARANCE; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG PROTEIN BINDING; ENANTIOMER; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HYDROGEN BOND; IC50; INTRINSIC CLEARANCE; LIPOPHILICITY; MICROSOME; MOUSE; NONHUMAN; PROTEIN PROTEIN INTERACTION; STEREOCHEMISTRY; STOICHIOMETRY; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; SUPERCRITICAL FLUID CHROMATOGRAPHY; TUMOR XENOGRAFT; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; DRUG SCREENING; LIVER MICROSOME; METABOLISM; STEREOISOMERISM; SYNTHESIS; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; HUMANS; LIGANDS; MICE; MICROSOMES, LIVER; POLYCOMB REPRESSIVE COMPLEX 2; PROTEIN BINDING; PYRROLIDINES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 85013974548     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2017.02.030     Document Type: Article

References (22)

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18. 15 For assay details, see the
19. For crystallization, data collection and structure refinement procedures, see the Supplementary Information.
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21. 18 It should be mentioned that two-diastereomer mixtures, (3R,4S) at the pyrrolidine but epimeric at the indane stereocenter as in 41 and 2, were used for biological characterization and in vivo studies due to synthetic availability. However, this could be justified by the fact that the two-diastereomer mixture of compounds such as 41 were virtually indistinguishable in our assays from the single diastereomer bearing an (S)-indane stereocenter (data not shown).
22. 19 For example, a 3 mg/kg intravenous dose of compound 2 in mouse had a total clearance of 1.7 L/h/kg and a half-life of 1 h with no oral bioavailability.