Design and Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for the Treatment of B-Cell Malignancies

  • J Med Chem. 2022 Jun 9;65(11):8011-8028. doi: 10.1021/acs.jmedchem.2c00530.
Jingbo Zhang  1  2 ,  Huimin Jiang  1 ,  Songwen Lin  1  2 ,  Deyu Wu  1  2 ,  Hua Tian  1  2 ,  Lin Jiang  1  2 ,  Yiman Cui  1  2 ,  Jing Jin  1 ,  Xiaoguang Chen  1 ,  Heng Xu  1  2
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.
PMID: 35609190 DOI: 10.1021/acs.jmedchem.2c00530
Abstract

Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to Other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced Apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant Anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ Inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.