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Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies
- Source :
- Journal of Medicinal Chemistry. 62:3898-3923
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
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....
- Subjects :
- Male
Ruxolitinib
Drug Evaluation, Preclinical
Mice, Nude
Histone Deacetylases
Rats, Sprague-Dawley
Mice
Structure-Activity Relationship
Pharmacokinetics
Catalytic Domain
Nitriles
Drug Discovery
medicine
Animals
Humans
Structure–activity relationship
Protein Kinase Inhibitors
Janus Kinases
Binding Sites
Chemistry
HDAC6
Xenograft Model Antitumor Assays
Rats
Histone Deacetylase Inhibitors
Molecular Docking Simulation
Pyrimidines
Cell culture
Hematologic Neoplasms
Toxicity
Cancer research
Pyrazoles
Molecular Medicine
Histone deacetylase
Janus kinase
Half-Life
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....9660d88d07416437e7552217ef401463