Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines

Blockage of more than one oncoprotein or pathway is now a standard approach in modern cancer therapy. Multiple inhibition is typically achieved with two or more drugs. Herein, we describe a pharmacophore merging strategy combining the JAK2/FLT3 inhibitor pacritnib with the pan-HDAC inhibitor, vorino...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-09, Vol.59 (18), p.8233-8262
Main Authors: Yang, Eugene Guorong, Mustafa, Nurulhuda, Tan, Eng Chong, Poulsen, Anders, Ramanujulu, Pondy Murugappan, Chng, Wee Joo, Yen, Jeffrey J. Y, Dymock, Brian W
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Bridged-Ring Compounds - chemistry
Bridged-Ring Compounds - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Hematologic Neoplasms - drug therapy
Hematologic Neoplasms - metabolism
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Humans
Janus Kinase 2 - antagonists & inhibitors
Models, Molecular
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyrimidines - chemistry
Pyrimidines - pharmacology
Signal Transduction - drug effects
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Summary:Blockage of more than one oncoprotein or pathway is now a standard approach in modern cancer therapy. Multiple inhibition is typically achieved with two or more drugs. Herein, we describe a pharmacophore merging strategy combining the JAK2/FLT3 inhibitor pacritnib with the pan-HDAC inhibitor, vorinostat, to create bispecific single molecules with both JAK and HDAC targeted inhibition. A preferred ether hydroxamate, 51, inhibits JAK2 and HDAC6 with low nanomolar potency, is 50-fold selective for JAK2 in a panel of 97 kinases. Broad cellular antiproliferative potency is supported by demonstration of JAK-STAT and HDAC pathway blockade in several hematological cell lines, inhibition of colony formation in HEL cells, and analysis of apoptosis. This study provides new tool compounds for further exploration of dual JAK–HDAC pathway inhibiton achieved with a single molecule.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00157