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
  • 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.

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