5U6D

Polycomb protein EED in complex with inhibitor: 2-[4-(4-{(3S,4R)-4-(dimethylamino)-1-[(2-fluoro-6-methylphenyl)methyl]pyrrolidin-3-yl}phenyl)-1H-pyrazol-1-yl]acetamide

Summary for 5U6D

• Entry DOI: 10.2210/pdb5u6d/pdb
• Related: 5U69
• Descriptor: Polycomb protein EED, 2-[4-(4-{(3S,4R)-4-(dimethylamino)-1-[(2-fluoro-6-methylphenyl)methyl]pyrrolidin-3-yl}phenyl)-1H-pyrazol-1-yl]acetamide (3 entities in total)
• Functional Keywords: wd40 prc2, protein binding, inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O75530
• Total number of polymer chains: 1
• Total formula weight: 43019.02

Authors

Jakob, C.G.,Zhu, H. (deposition date: 2016-12-07, release date: 2017-03-15, Last modification date: 2023-10-04)

Primary citation

Curtin, M.L.,Pliushchev, M.A.,Li, H.Q.,Torrent, M.,Dietrich, J.D.,Jakob, C.G.,Zhu, H.,Zhao, H.,Wang, Y.,Ji, Z.,Clark, R.F.,Sarris, K.A.,Selvaraju, S.,Shaw, B.,Algire, M.A.,He, Y.,Richardson, P.L.,Sweis, R.F.,Sun, C.,Chiang, G.G.,Michaelides, M.R.
SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.
Bioorg. Med. Chem. Lett., 27:1576-1583, 2017

PubMed 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.

PubMed: 28254486
DOI: 10.1016/j.bmcl.2017.02.030

Experimental method

X-RAY DIFFRACTION (1.64 Å)