2. Academic Validation
  3. Design, synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors

Design, synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors

  • Bioorg Med Chem. 2020 Mar 15;28(6):115354. doi: 10.1016/j.bmc.2020.115354.
Dezhong Ji 1,  Wanwan Zhang 1,  Yungen Xu 2,  Jing-Jing Zhang 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 32063403 DOI: 10.1016/j.bmc.2020.115354
Abstract

A series of anthranilamide derivatives were designed and synthesized as novel smoothened (Smo) inhibitors based on the Smo Inhibitor taladegib (LY2940680), which can also inhibit the SMO-D473H mutant, via a ring-opening strategy. The phthalazine core in LY2940680 was replaced with anthranilamide, which retained the inhibitory activity towards the Hedgehog (Hh) signaling pathway as evidenced by a dual luciferase reporter gene assay. Compound 12a displayed the best inhibitory activity against the Hh signaling pathway with IC50 value of 34.09 nM, and exhibited better proliferation inhibitory activity towards the Daoy cell line (IC50 = 0.48 μM) than LY2940680 (IC50 = 0.79 μM).

Keywords

Anthranilamide; Hedgehog signaling pathway; Molecular dynamics; Ring-opening; Smoothened inhibitor.

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