Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for Cancer Immunotherapy

  • J Med Chem. 2025 Jul 24;68(14):14859-14881. doi: 10.1021/acs.jmedchem.5c01036.
Songwen Lin  1  2  3 ,  Nan Xiang  4  5 ,  Wenqian Liu  1  2  3 ,  Deyu Wu  1  2  3 ,  Yiran Chen  1 ,  Tianning Xiong  1  2  3 ,  Junpu Ge  6 ,  Wen Zhou  1  2  3 ,  Hua Tian  1  2  3 ,  Kehui Zhang  1  2  3 ,  Li Sheng  6 ,  Jing Jin  1 ,  Hongbo Wang  4  5 ,  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 Substance 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. Key laboratory of Molecular Pharmacology and Drug Evalution, Ministry of Education, Yantai University, Yantai 264005, China.
  • 5. Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 6. 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: 40662664 DOI: 10.1021/acs.jmedchem.5c01036
Abstract

Phosphoinositide 3-kinase δ (PI3Kδ) exerts a pivotal influence on tumor microenvironment, emphasizing its significance in Cancer Immunotherapy. Herein, a series of novel thienopyrimidine derivatives was designed as potent and selective PI3Kδ inhibitors. Extensive structure-activity relationship studies yielded two lead compounds 18 and 42 with remarkable single-digit nanomolar potencies against PI3Kδ and over 100-fold selectivity relative to Other class-I PI3K isoforms. 18 and 42 efficiently inhibited Akt Ser473 phosphorylation in the time- and concentration-dependent manner in mouse B16F10 cells. Mechanistic investigations revealed that 18 and 42 directly suppressed Treg cells and downregulated the expression of PD-L1 in the in vitro settings. With favorable pharmacokinetic properties, 18 underwent further evaluation in B16F10 melanoma and Lewis lung carcinoma mouse models, demonstrating significant in vivo Anticancer efficacy by reducing tumor-infiltrating Treg cells and thereby enhancing immune responses. This study collectively highlights the potential of PI3Kδ selective inhibitors as promising candidates toward Cancer Immunotherapy.

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