Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 20, Pages 8336-8357Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00678
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Funding
- National Medical Research Council of Singapore (NMRC CBRG)
- NMRC Clinician Scientist Investigator Award
- Singapore Cancer Syndicate Grant
- National Research Foundation Singapore
- Singapore Ministry of Education under Research Centers of Excellence initiative
- Ministry of Science and Technology, Taiwan [NSC 102-2320-B-001-007-MY3]
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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 (l), 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 IC(50)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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