2. Academic Validation
  3. Design and Synthesis of Ligand Efficient Dual Inhibitors of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Based on Ruxolitinib and Vorinostat

Design and Synthesis of Ligand Efficient Dual Inhibitors of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Based on Ruxolitinib and Vorinostat

  • J Med Chem. 2017 Oct 26;60(20):8336-8357. doi: 10.1021/acs.jmedchem.7b00678.
Lianbin Yao 1,  Nurulhuda Mustafa 2,  Eng Chong Tan 3 4,  Anders Poulsen 5 6,  Prachi Singh 7,  Minh-Dao Duong-Thi 7,  Jeannie X T Lee 2,  Pondy Murugappan Ramanujulu 1 8,  Wee Joo Chng 2 9 10,  Jeffrey J Y Yen 3,  Sten Ohlson 7,  Brian W Dymock 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, National University of Singapore , 18 Science Drive 4, 117543, Singapore.
  • 2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , 1E Kent Ridge Road, NUHS Tower Block Level 10, 117549, Singapore.
  • 3 Institute of Biomedical Sciences, Academia Sinica , Taipei 115, Taiwan.
  • 4 Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica , Taipei, 115, Taiwan.
  • 5 Experimental Therapeutics Centre , 31 Biopolis Way, 03-01 Nanos, 138669, Singapore.
  • 6 Department of Chemistry, National University of Singapore , 3 Science Drive 3, 117543, Singapore.
  • 7 School of Biological Sciences, Nanyang Technological University (NTU) , 637551, Singapore.
  • 8 Centre for Life Sciences Level 5, Life Sciences Institute, National University of Singapore , 28 Medical Drive, 117456, Singapore.
  • 9 Cancer Science Institute, National University of Singapore , 117599, Singapore.
  • 10 National University Cancer Institute of Singapore, National University Health System , 119074, Singapore.
PMID: 28953386 DOI: 10.1021/acs.jmedchem.7b00678
Abstract

Concomitant inhibition of multiple oncogenic pathways is a desirable goal in Cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC Inhibitor vorinostat (2), leading to new molecules that are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1, 2, 3, 6, and 10 with IC50 values of less than 20 nM, is <100 nM potent against JAK2 and HDAC11, and is selective for the JAK family against a panel of 97 kinases. Broad cellular antiproliferative potency of 24 is supported by demonstration of JAK-STAT and HDAC pathway blockade in hematological cell lines. Methyl analogue 45 has an even more selective profile. This study provides new leads for assessment of JAK and HDAC pathway dual inhibiton achieved with a single molecule.

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