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

Tao Yang; Mengshi Hu; Yong Chen; Mingli Xiang; Minghai Tang; Wenyan Qi; Mingsong Shi; Jun He; Xue Yuan; Chufeng Zhang; Kongjun Liu; Jiewen Li; Zhuang Yang; Lijuan Chen

doi:10.1021/acs.jmedchem.0c01488

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. Epub 2020 Nov 30.

Authors

Tao Yang¹, Mengshi Hu¹, Yong Chen¹, Mingli Xiang¹, Minghai Tang¹, Wenyan Qi¹, Mingsong Shi¹, Jun He¹, Xue Yuan¹, Chufeng Zhang¹, Kongjun Liu¹, Jiewen Li¹, Zhuang Yang^{1

2}, Lijuan Chen^{1

2}

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/F3^V617F cells (high expression of JAK2^V617F 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-JAK2^V617F allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Female
Humans
Isoquinolines / chemical synthesis
Isoquinolines / metabolism
Isoquinolines / pharmacokinetics
Isoquinolines / therapeutic use*
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / metabolism
Male
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, SCID
Molecular Docking Simulation
Molecular Structure
Myeloproliferative Disorders / drug therapy
Neoplasms / drug therapy*
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use*
Rats, Sprague-Dawley
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Isoquinolines
Protein Kinase Inhibitors
Pyrimidines
Janus Kinase 2