2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel bivalent PI3K inhibitors for the potential treatment of cancer

Design, synthesis, and biological evaluation of novel bivalent PI3K inhibitors for the potential treatment of cancer

  • Bioorg Chem. 2023 Nov;140:106814. doi: 10.1016/j.bioorg.2023.106814.
Liang Xia 1,  Lin Jiang 1,  Tingting Du 2,  Songwen Lin 1,  Tianning Xiong 1,  Shouguo Peng 1,  Hua Tian 1,  Kehui Zhang 1,  Deyu Wu 1,  Li Sheng 3,  Ming Ji 4,  Xiaoguang Chen 2,  Heng Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: jiming@imm.ac.cn.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: xuheng@imm.ac.cn.
PMID: 37657197 DOI: 10.1016/j.bioorg.2023.106814
Abstract

Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in Cancer and has become a key target for Cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K Inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent Anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.

Keywords

Anti-cancer activity; Bivalent inhibitor; Phosphoinositide 3-kinase; Structure-activity relationship.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149521
    PI3K Inhibitor