Discovery of novel 7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines as ATR inhibitors based on structure-based drug design

  • Eur J Med Chem. 2022 Nov 26;246:114945. doi: 10.1016/j.ejmech.2022.114945.
Yinliang Qi  1 ,  Kun Wang  1 ,  Bin Long  1 ,  Hao Yue  1 ,  Yongshuo Wu  1 ,  Dexiao Yang  2 ,  Minghui Tong  2 ,  Xuan Shi  2 ,  Yunlei Hou  3 ,  Yanfang Zhao  4
Affiliations
  • 1. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China.
  • 2. 3D BioOptima, 1338 Wuzhong Avenue, Suzhou, 215104, China.
  • 3. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China. Electronic address: [email protected].
  • 4. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China. Electronic address: [email protected].
PMID: 36462444 DOI: 10.1016/j.ejmech.2022.114945
Abstract

ATR kinase is essential to the viability of replicating cells responding to the accumulation of single-strand breaks in DNA, which is an attractive Anticancer drug target based on synthetic lethality. Herein we design, synthesize, and evaluate a novel series of fused pyrimidine derivatives as ATR inhibitors. As a result, compound 48f, with an IC50 value of 0.0030 μM against ATR, displayed strong monotherapy efficacy in ataxia-telangiectasia mutated (ATM) kinase-deficient tumor cells LoVo, SW620, OVCAR-3 cell lines with IC50 values of 0.040 μM, 0.095 μM, 0.098 μM, respectively. More importantly, the combination of 48f with AZD-1390, cisplatin, oxaliplatin, and olaparib respectively resulted in synergistic activity against HT-29, HCT116, A549, MCF-7, MDA-MB-231 cells. Moreover, 48f showed a favorable pharmacokinetic profile with a bioavailability of 30.0% in SD rats, acceptable PPB, high permeability (Papp A to B = 8.23 cm s-1 × 10-6), and low risk of drug-drug interactions. Collectively, compound 48f could be a promising compound for further investigation.

Keywords
ATR inhibitors; Anticancer activity; Fused pyrimidine derivatives; Synthetic lethality.
Products