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ACS medicinal chemistry letters
Feb 13, 2020;11 (2): 133-140.

Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

Dai-Shi Su, Junya Qu, Mark Schulz, Chuck W Blackledge, Hongyi Yu, Jenny Zeng, Joelle Burgess, Alexander Reif, Melissa Stern, Raman Nagarajan, Melissa Baker Pappalardi, Kristen Wong, Alan P Graves, William Bonnette, Liping Wang, Patricia Elkins, Beth Knapp-Reed, Jeffrey D Carson, Charles McHugh, Helai Mohammad, Ryan Kruger, Juan Luengo, Dirk A Heerding, Caretha L Creasy
Author Information
  1. Dai-Shi Su: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  2. Junya Qu: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  3. Mark Schulz: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  4. Chuck W Blackledge: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  5. Hongyi Yu: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  6. Jenny Zeng: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  7. Joelle Burgess: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  8. Alexander Reif: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  9. Melissa Stern: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  10. Raman Nagarajan: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  11. Melissa Baker Pappalardi: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  12. Kristen Wong: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  13. Alan P Graves: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  14. William Bonnette: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  15. Liping Wang: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  16. Patricia Elkins: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  17. Beth Knapp-Reed: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  18. Jeffrey D Carson: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  19. Charles McHugh: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  20. Helai Mohammad: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  21. Ryan Kruger: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  22. Juan Luengo: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  23. Dirk A Heerding: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  24. Caretha L Creasy: Medicinal Chemistry, Medicine Design, Oncology R&D, Data and Computational Sciences, and Protein Cellular and Structural Sciences, Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
PMID: 32071679 DOI: 10.1021/acsmedchemlett.9b00493

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 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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