2. Academic Validation
  3. N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

  • J Med Chem. 2020 Dec 10;63(23):14921-14936. doi: 10.1021/acs.jmedchem.0c01488.
Tao Yang 1,  Mengshi Hu 1,  Yong Chen 1,  Mingli Xiang 1,  Minghai Tang 1,  Wenyan Qi 1,  Mingsong Shi 1,  Jun He 1,  Xue Yuan 1,  Chufeng Zhang 1,  Kongjun Liu 1,  Jiewen Li 1,  Zhuang Yang 1 2,  Lijuan Chen 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 2 Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
PMID: 33256400 DOI: 10.1021/acs.jmedchem.0c01488
Abstract

In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the superior derivative 13ac. Compound 13ac showed excellent potency on JAK2 kinase, SET-2, and Ba/F3V617F cells (high expression of JAK2V617F mutation) with IC50 values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound 13ac could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound 13ac also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, 13ac significantly ameliorated the disease symptoms in a Ba/F3-JAK2V617F allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.

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