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J Med Chem. 2016 Sep 22;59(18):8233-62. doi: 10.1021/acs.jmedchem.6b00157. Epub 2016 Sep 8.

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.

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Department of Pharmacy, National University of Singapore , 18 Science Drive 4, Singapore 117543.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , 1E Kent Ridge Road, NUHS Tower Block Level 10, Singapore 119228.
Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
Experimental Therapeutics Centre , 31 Biopolis Way, 03-01 Nanos, Singapore 138669.
Department of Chemistry, National University of Singapore , 3 Science Drive 3, Singapore 117543.
Life Sciences Institute, National University of Singapore , Centre for Life Sciences, Level 5, 28 Medical Drive, Singapore 117456.
Cancer Science Institute, Singapore, National University of Singapore , Singapore 117599.
National University Cancer Institute of Singapore, National University Health System Singapore 119074.


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 <100 nM potent against HDACs 2 and 10, submicromolar potent against HDACs 1, 8, and 11, and >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.

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