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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00157

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.