2. Academic Validation
  3. Discovery of Hexahydrofuro[3,2- b]furans as New Kinase-Selective and Orally Bioavailable JAK3 Inhibitors for the Treatment of Leukemia Harboring a JAK3 Activating Mutant

Discovery of Hexahydrofuro[3,2- b]furans as New Kinase-Selective and Orally Bioavailable JAK3 Inhibitors for the Treatment of Leukemia Harboring a JAK3 Activating Mutant

  • J Med Chem. 2022 Aug 11;65(15):10674-10690. doi: 10.1021/acs.jmedchem.2c00922.
Shan Li 1,  Hongfei Si 1,  Xiaojuan Song 2,  Chong Lei 3,  Xiaoqiang He 1,  Jie Wang 1,  Yiling Liu 1,  Yang Zhou 1,  Jian-Guo Song 1,  Lijie Peng 1,  Xia Tang 1,  Shingpan Chan 4,  Xiaomei Ren 1,  Zhengchao Tu 2,  Zhengqiu Li 1,  Zhen Wang 3,  Zhang Zhang 1,  Ke Ding 1 3 5 6
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
  • 2 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
  • 3 State Key Laboratory of Bioorganic Chemistry and Natural Products, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
  • 4 Guangzhou Lixin Pharmaceuticals, Guangzhou 510530, China.
  • 5 The First Affiliated Hospital (Huaqiao Hospital), Jinan University, #601 Huangpu Avenue West, Guangzhou 510632, China.
  • 6 Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China.
PMID: 35860875 DOI: 10.1021/acs.jmedchem.2c00922
Abstract

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound 12n potently inhibited JAK3 kinase activity with an IC50 value of 1.2 nM and was more than 900-fold selective over JAK1, JAK2, and Tyk2. Cell-based assays revealed that 12n significantly suppressed phosphorylation of JAK3 and the downstream effectors STAT3/5 and also robustly restrained proliferation of BaF3 cells transfected with JAK3M511I activating mutation and human leukemia U937 cells harboring JAK3M511I with IC50 values of 22.9 and 20.2 nM, respectively. More importantly, 12n showed reasonable pharmacokinetic (PK) properties, and oral administration of 12n at a dose of 50 mg/kg twice daily led to tumor regression in a U937 cell inoculated xenograft mouse model. Thus, 12n represents a promising lead compound for further optimization to discover new therapeutic agents for hematological malignancies.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150688
    JAK3 Inhibitor
    JNK