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

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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.

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    Further chemical optimization by changing the 2-methylpyridine of 40 to 1-methylpyrazole provided compound 41 with a three-fold boost in EED binding potency (Kd = 0.9 μM) and enhanced cellular activity (IC50 = 2.1 μM) (Fig. 15). Researchers from AbbVie Inc. identified compound 42 (EED709) as a modestly potent EED inhibitor (Ki = 600 nM) through a high-throughput TSA-based screen against EED protein (Fig. 16A) [99]. As shown in Fig. 16B, the co-crystal structure of EED709 in complex with EED revealed that compound EED709 occupied the H3K27me3 binding pocket, which was obviously remodeled to accommodate the pyrrolidine ligand.

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Current address: eFFECTOR Therapeutics, 11180 Roselle St., Suite A, San Diego, CA 92121, United States.

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