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Design, Synthesis, and Biological Evaluation of Lysine Demethylase 5 C Degraders
Author(s) -
Iida Tetsuya,
Itoh Yukihiro,
Takahashi Yukari,
Yamashita Yasunobu,
Kurohara Takashi,
Miyake Yuka,
Oba Makoto,
Suzuki Takayoshi
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000933
Subject(s) - demethylase , chemistry , epigenetics , computational biology , biology , biochemistry , gene
Lysine demethylase 5 C (KDM5C) controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics. KDM5C has emerged as a therapeutic target for anti‐prostate cancer agents, and recently we identified triazole 1 as an inhibitor of KDM5C. Compound 1 exhibited highly potent KDM5C‐inhibitory activity in in vitro enzyme assays, but did not show strong anticancer effects. Therefore, a different approach is needed for the development of anticancer agents targeting KDM5C. Here, we attempted to identify KDM5C degraders by focusing on a protein‐knockdown strategy. Compound 3 b , which was designed based on compound 1 , degraded KDM5C and inhibited the growth of prostate cancer PC‐3 cells more strongly than compound 1 . These findings suggest that KDM5C degraders are more effective as anticancer agents than compounds that only inhibit the catalytic activity of KDM5C.