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Bioorg Med Chem Lett. 2017 Apr 1;27(7):1576-1583. doi: 10.1016/j.bmcl.2017.02.030. Epub 2017 Feb 20.

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

Author information

1
AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: mike.curtin@abbvie.com.
2
AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, United States.

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.

KEYWORDS:

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

PMID:
28254486
DOI:
10.1016/j.bmcl.2017.02.030
[Indexed for MEDLINE]

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