Discovery of JMJD7 inhibitors with the aid of virtual screening and bioactivity evaluation

  • Bioorg Med Chem Lett. 2021 Aug 1;45:128139. doi: 10.1016/j.bmcl.2021.128139.
Wenqing Zhang  1 ,  Kan Li  2 ,  Tianqi Wang  2 ,  Ming Wu  2 ,  Linli Li  3
Affiliations
  • 1. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, 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. Electronic address: [email protected].
PMID: 34048880 DOI: 10.1016/j.bmcl.2021.128139
Abstract

Jumonji-C (JmjC) domain-containing 7 (JMJD7), which is a 2-oxoglutarate (2OG)-dependent oxygenase, has been demonstrated to play an important role in the occurrence and development of a number of diseases, particularly Cancer. Discovery of JMJD7 inhibitors is thus of great importance. Herein consensus docking/scoring strategy and bioactivity evaluation were used to identify JMJD7 inhibitors from various chemical databases. Seven active compounds were retrieved. The most potent compound, Cpd-3, showed an IC50 value of 6.62 μM against JMJD7. Further biophysical assays confirmed that Cpd-3 could efficiently bind to JMJD7 in vitro. Flexible docking was used to predict the binding mode of Cpd-3 with JMJD7. In a cellular assay, Cpd-3 displayed good inhibitory activity against Cancer cell lines expressing a high level of JMJD7. As far as we know, Cpd-3 is the first JMJD7 inhibitor reported so far. Overall, this study established a good starting point for drug discovery targeting JMJD7.

Keywords
Consensus docking; Epigenetics; JMJD7; Small molecule inhibitor; Virtual screening.
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