2. Academic Validation
  3. Design, Synthesis, and Bioevaluation of Novel Reversibly Photoswitchable PI3K Inhibitors Based on Phenylazopyridine Derivatives toward Light-Controlled Cancer Treatment

Design, Synthesis, and Bioevaluation of Novel Reversibly Photoswitchable PI3K Inhibitors Based on Phenylazopyridine Derivatives toward Light-Controlled Cancer Treatment

  • J Med Chem. 2024 Feb 20. doi: 10.1021/acs.jmedchem.3c01864.
Yan Zhang 1 2 3,  Jialing Deng 1 2 3,  Hua Tian 1 2 3,  Haixiang Qi 1 2 3,  Tianning Xiong 1 2 3,  Songwen Lin 1 2 3,  Yi Dong 1 2 3,  Lijun Luo 4,  Deyu Wu 1 2 3,  Kehui Zhang 1 2 3,  Ming Ji 1 3,  Tingting Du 1 3,  Li Sheng 4,  Xiaoguang Chen 1 3,  Heng Xu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 4 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 38377311 DOI: 10.1021/acs.jmedchem.3c01864
Abstract

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161301
    PI3K Inhibitor