Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzofuran IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma

Yun Chen; Yi Ning; Zhiwei Chen; Yaping Xue; Qingyun Wu; Wenhu Duan; Jian Ding; Jinpei Zhou; Hua Xie; Huibin Zhang

doi:10.1016/j.ejmech.2023.115453

Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzofuran IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma

Eur J Med Chem. 2023 Aug 5:256:115453. doi: 10.1016/j.ejmech.2023.115453. Epub 2023 May 5.

Authors

Yun Chen¹, Yi Ning², Zhiwei Chen³, Yaping Xue⁴, Qingyun Wu¹, Wenhu Duan³, Jian Ding⁴, Jinpei Zhou⁵, Hua Xie⁶, Huibin Zhang⁷

Affiliations

¹ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, 210009, PR China.
² Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
³ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, PR China.
⁴ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, PR China.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: zhjp@cpu.edu.cn.
⁶ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, PR China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, PR China. Electronic address: hxie@simm.ac.cn.
⁷ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: zhanghb80@cpu.edu.cn.

PMID: 37163947
DOI: 10.1016/j.ejmech.2023.115453

Abstract

Interleukin-1 receptor associated kinase 4 (IRAK4) is a critical mediator of MYD88 L265P-induced NF-κB activation, indicating it is a promising therapeutic target for diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of 2,3-dihydrobenzofuran IRAK4 inhibitors through structure-based drug design. The representative compound 22 exhibited strong IRAK4 inhibitory potency (IRAK4 IC₅₀ = 8.7 nM), favorable kinase selectivity and high antiproliferative activity against the MYD88 L265P DLBCL cell line (OCI-LY10 IC₅₀ = 0.248 μM). Compound 22 also exhibited the ability to inhibit the activation of IRAK4 signaling pathway and induce apoptosis in MYD88 L265P DLBCL cell line. In combination with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, 22 showed enhanced apoptosis-inducing effect and antiproliferative potency. The most advanced compound 22 in this inhibitor series holds promise for further development into efficacious and selective IRAK4 inhibitors for the treatment of DLBCL.

Keywords: 2,3-Dihydrobenzofuran; Apoptosis; Diffuse large B-Cell lymphoma; Interleukin-1 receptor associated kinase 4; Structure-based drug design.

MeSH terms

Cell Line, Tumor
Humans
Interleukin-1 Receptor-Associated Kinases*
Lymphoma, Large B-Cell, Diffuse* / metabolism
Myeloid Differentiation Factor 88 / metabolism

Substances

Interleukin-1 Receptor-Associated Kinases
Myeloid Differentiation Factor 88
coumaran
IRAK4 protein, human