Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6)

• Published in: Bioorganic & medicinal chemistry letters 2018-08, Vol.28 (15), p.2636-2640
• Main Authors: Yao, Lianbin, Ramanujulu, Pondy Murugappan, Poulsen, Anders, Ohlson, Sten, Dymock, Brian W.
• Format: Article
• Language: English
• Subjects: Designed Multiple Ligand; Histone Deacetylase; Janus kinase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.06.037

[Display omitted] 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.