Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors

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 op...

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Published inACS medicinal chemistry letters Vol. 11; no. 2; pp. 133 - 140
Main Authors Su, Dai-Shi, Qu, Junya, Schulz, Mark, Blackledge, Chuck W, Yu, Hongyi, Zeng, Jenny, Burgess, Joelle, Reif, Alexander, Stern, Melissa, Nagarajan, Raman, Pappalardi, Melissa Baker, Wong, Kristen, Graves, Alan P, Bonnette, William, Wang, Liping, Elkins, Patricia, Knapp-Reed, Beth, Carson, Jeffrey D, McHugh, Charles, Mohammad, Helai, Kruger, Ryan, Luengo, Juan, Heerding, Dirk A, Creasy, Caretha L
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.02.2020
Amer Chemical Soc
American Chemical Society (ACS)
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
inhibitors
isoxazole amides
SMYD3
MEKK2
OVEREXPRESSION
CANCER
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Summary: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.
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INDUSTRY
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.9b00493