Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6) |
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Authors: | Lianbin Yao Pondy Murugappan Ramanujulu Anders Poulsen Sten Ohlson Brian W Dymock |
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Institution: | 1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore;2. Life Sciences Institute, Centre for Life Sciences Level 5, 28 Medical Drive, National University of Singapore, Singapore;3. Experimental Therapeutics Centre, 31 Biopolis Way, 03-01 Nanos, Singapore;4. School of Biological Sciences, Nanyang Technological University (NTU), Singapore |
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Abstract: | Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1. A preferred compound, 13b, had unprecedented sub-nanomolar JAK2 potency with an IC50 of 41?pM and a sub-nanomolar IC50 against HDAC6 of 200?pM. Binding models show a good fit into both JAK2 and HDAC6. |
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Keywords: | Janus kinase Histone Deacetylase Designed Multiple Ligand |
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