2. Academic Validation
  3. Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6)

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

  • Bioorg Med Chem Lett. 2018 Aug 15;28(15):2636-2640. doi: 10.1016/j.bmcl.2018.06.037.
Lianbin Yao 1,  Pondy Murugappan Ramanujulu 2,  Anders Poulsen 3,  Sten Ohlson 4,  Brian W Dymock 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore.
  • 2 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore; 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.
  • 5 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore. Electronic address: [email protected].
PMID: 29945795 DOI: 10.1016/j.bmcl.2018.06.037
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.

Keywords

Designed Multiple Ligand; Histone Deacetylase; Janus kinase.

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