2. Academic Validation
  3. Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies

Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies

  • J Med Chem. 2019 Apr 25;62(8):3898-3923. doi: 10.1021/acs.jmedchem.8b01597.
Xuewu Liang 1 2,  Jie Zang 1,  Xiaoyang Li 3,  Shuai Tang 2,  Min Huang 2,  Meiyu Geng 2,  C James Chou 3,  Chunpu Li 2,  Yichun Cao 4,  Wenfang Xu 1,  Hong Liu 2,  Yingjie Zhang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy , Shandong University , Ji'nan , Shandong 250012 , P. R. China.
  • 2 State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road , Shanghai 201203 , China.
  • 3 Department of Drug Discovery and Biomedical Sciences, College of Pharmacy , Medical University of South Carolina , Charleston , South Carolina 29425 , United States.
  • 4 School of Pharmacy , Fudan University , 826 Zhanghen Road , Shanghai 201203 , China.
PMID: 30901208 DOI: 10.1021/acs.jmedchem.8b01597
Abstract

Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC Inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2V617F mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.

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