Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma

  • Eur J Med Chem. 2020 Mar 15;190:112092. doi: 10.1016/j.ejmech.2020.112092.
Yun Chen  1 ,  Gang Bai  2 ,  Yi Ning  3 ,  Shi Cai  4 ,  Tao Zhang  3 ,  Peiran Song  3 ,  Jinpei Zhou  5 ,  Wenhu Duan  6 ,  Jian Ding  2 ,  Hua Xie  7 ,  Huibin Zhang  8
Affiliations
  • 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, PR China.
  • 2. 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; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, PR China.
  • 3. 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.
  • 4. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 5. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 6. 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.
  • 7. 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. Electronic address: [email protected].
  • 8. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 32014679 DOI: 10.1016/j.ejmech.2020.112092
Abstract

Harboring MyD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MyD88 signaling. Herein, we report the design, synthesis, and structure-activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell-like (ABC) subtype DLBCL with MyD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and Btk Inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 Inhibitor for the treatment of mutant MyD88 DLBCL.

Keywords
Antitumor agents; Diffuse large B-cell lymphoma; Drug design; Imidazo[1,2-b]pyridazine; Interleukin-1 receptor associated kinase 4.
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