Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC

Siqi Guo; Tongguan Jia; Xiaoming Xu; Feng Yang; Senhao Xiao; Zeng Hou; Hesong Xu; Shuyuan Ma; Xiao Liu; Cheng Luo; Hualiang Jiang; Hua Chen; Shijie Chen

doi:10.1016/j.ejmech.2023.115093

Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC

Eur J Med Chem. 2023 Feb 15:248:115093. doi: 10.1016/j.ejmech.2023.115093. Epub 2023 Jan 10.

Authors

Siqi Guo¹, Tongguan Jia², Xiaoming Xu², Feng Yang³, Senhao Xiao³, Zeng Hou⁴, Hesong Xu⁴, Shuyuan Ma⁴, Xiao Liu⁵, Cheng Luo⁴, Hualiang Jiang⁶, Hua Chen⁷, Shijie Chen⁸

Affiliations

¹ School of Pharmacy, Nanchang University, Nanchang, 330006, Jiangxi, China; Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, 071002, China.
³ Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
⁵ Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
⁶ School of Pharmacy, Nanchang University, Nanchang, 330006, Jiangxi, China; Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: hljiang@simm.ac.cn.
⁷ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding, 071002, China. Electronic address: hua-todd@163.com.
⁸ Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: shijiechen@simm.ac.cn.

PMID: 36645983
DOI: 10.1016/j.ejmech.2023.115093

Abstract

Eleven-Nineteen-Leukemia Protein (ENL) containing YEATS domain, a potential drug target, has emerged as a reader of lysine acetylation. SGC-iMLLT bearing with benzimidazole scaffold was identified as an effective ENL inhibitor, but with weak activity against mixed-lineage leukemia (MLL)-rearranged cells proliferation. In this study, a series of compounds were designed and synthesized by structural optimization on SGC-iMLLT. All the compounds have been evaluated for their ENL inhibitory activities. The results showed that compounds 13, 23 and 28 are the most potential ones with the IC₅₀ values of 14.5 ± 3.0 nM, 10.7 ± 5.3 nM, and 15.4 ± 2.2 nM, respectively, similar with that of SGC-iMLLT. They could interact with ENL protein and strengthen its thermal stability in vitro. Among them, compound 28 with methyl phenanthridinone moiety replacement of indazole in SGC-iMLLT, exhibited significantly inhibitory activities towards MV4-11 and MOLM-13 cell lines with IC₅₀ values of 4.8 μM and 8.3 μM, respectively, exhibiting ∼7 folds and ∼9 folds more potent inhibition of cell growth than SGC-iMLLT. It could also increase the ENL thermal stability while SGC-iMLLT had no obvious effect on leukemia cells. Moreover, compound 28 could downregulate the expression of target gene MYC either alone or in combination with JQ-1 in cells, which was more effective than SGC-iMLLT. Besides, in vivo pharmacokinetic studies showed that the PK properties for compound 28 was much improved over that of SGC-iMLLT. These observations suggested compound 28 was a potential ligand for ENL-related MLL chemotherapy.

Keywords: Acute myeloid leukemia; Benzimidazole derivatives; ENL Inhibitor; Histone lysine acetylation; YEATS domain.

MeSH terms

Cell Line
Histones / metabolism
Humans
Leukemia* / drug therapy
Leukemia* / metabolism
Myeloid-Lymphoid Leukemia Protein / metabolism
Protein Domains
Transcription Factors* / metabolism

Substances

Histones
Myeloid-Lymphoid Leukemia Protein
Transcription Factors
ELL protein, human