2. Academic Validation
  3. Design, synthesis and biological evaluation of 2-aminopyrimidine-based LSD1 inhibitors

Design, synthesis and biological evaluation of 2-aminopyrimidine-based LSD1 inhibitors

  • Bioorg Chem. 2022 Apr;121:105699. doi: 10.1016/j.bioorg.2022.105699.
Xinran Wang 1,  Cai Zhang 2,  Xiangyu Zhang 3,  Jiming Wang 3,  Liyu Zhao 3,  Dongmei Zhao 4,  Maosheng Cheng 3
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Chaoyang District, Beijing 102488, China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 102488, China.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: medchemzhao@163.com.
PMID: 35219044 DOI: 10.1016/j.bioorg.2022.105699
Abstract

AZD9291, with excellent pharmaceutical properties, has been reported to have certain LSD1 inhibitory activity. Therefore, we carried out structural optimization based on the AZD9291 skeleton to increase the LSD1 inhibitory potential of the compound. Then, a series of 2-aminopyrimidine derivatives were designed and synthesized as LSD1 inhibitors, and their structure-activity relationships were studied. The most promising compound, X43, with an IC50 of 0.89 μM showed remarkable LSD1 selectivity not only to EGFRwt (>100-fold) but also to MAO-A/B (>50-fold). Further studies showed that X43 inhibited LSD1 activity and induced the Apoptosis of A549 cells in a dose-dependent manner. Meanwhile, compound X43 showed a superior ability to inhibit the proliferation of A549 and THP-1 cells, with IC50 values of 1.62 μM and 1.21 μM, respectively. Then, analyses of the stability of human liver microsomes, CYP inhibition and in vivo pharmacokinetics in rats showed that X43 had favorable profiles in vitro and in vivo and the potential for further study. Our findings suggested that a 2-aminopyrimidine-based LSD1 inhibitor deserves further investigation as a treatment for LSD1-overexpressing Cancer.

Keywords

2-Aminopyrimidine; LSD1 inhibitors; Molecular docking; Structure-activity relationships.

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