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Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

ABSTRACT: We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.

SUBMITTER: Su DS

PROVIDER: S-EPMC7025381 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

Su Dai-Shi DS Qu Junya J Schulz Mark M Blackledge Chuck W CW Yu Hongyi H Zeng Jenny J Burgess Joelle J Reif Alexander A Stern Melissa M Nagarajan Raman R Pappalardi Melissa Baker MB Wong Kristen K Graves Alan P AP Bonnette William W Wang Liping L Elkins Patricia P Knapp-Reed Beth B Carson Jeffrey D JD McHugh Charles C Mohammad Helai H Kruger Ryan R Luengo Juan J Heerding Dirk A DA Creasy Caretha L CL

ACS medicinal chemistry letters 20191227 2

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound <b>1</b> provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profil ...[more]

PMID: 32071679

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