2. Academic Validation
  3. Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors

Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors

  • Bioorg Med Chem Lett. 2017 Jul 15;27(14):3201-3204. doi: 10.1016/j.bmcl.2017.05.002.
Zhen Fang 1,  Tian-Qi Wang 2,  Hui Li 1,  Guo Zhang 3,  Xiao-Ai Wu 1,  Li Yang 1,  Yu-Lan Peng 1,  Jun Zou 1,  Lin-Li Li 3,  Rong Xiang 4,  Sheng-Yong Yang 5
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
  • 4 Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: rxiang@nankai.edu.cn.
  • 5 Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: yangsy@scu.edu.cn.
PMID: 28539219 DOI: 10.1016/j.bmcl.2017.05.002
Abstract

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41±0.03μM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.

Keywords

Epigenetics; Histone lysine demethylase; KDM4D; Small molecule inhibitor; Structure-activity relationship.

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