Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 158, Issue -, Pages 593-619Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.09.024
Keywords
Multicomponent ligand; JAK2 inhibitor; HDAC inhibitor; JAK/HDAC dual inhibitor
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Funding
- Singapore National Medical Research Council (NMRC CBRG) [NMRC/CBRG12Nov114]
- NMRC Clinician Scientist Investigator award
- Singapore Cancer Syndicate Grant
- National Research Foundation Singapore
- Singapore Ministry of Education
- Ministry of Science and Technology, Taiwan [NSC 102-2320-B-001-007-MY3]
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Specifically blocking more than one oncogenic pathway simultaneously in a cancer cell with a combination of different drugs is the mainstay of the majority of cancer treatments. Being able to do this via two targeted pathways without inducing side effects through a general mechanism, such as chemotherapy, could bring benefit to patients. In this work we describe a new dual inhibitor of the JAK-STAT and HDAC pathways through designing and developing two types of molecule based on the JAK2 selective inhibitor XL019 and the pan-HDAC inhibitor, vorinostat. Both series of compounds had examples with low nanomolar JAK2 and HDAC1/6 inhibition. In some cases good HDAC1 selectivity was achieved while retaining HDAC6 activity. The observed potency is explained through molecular docking studies of all three enzymes. One example, 69c had 16-25 fold selectivity against the three other JAK-family proteins JAK1, JAK3 and TYK2. A number of compounds had sub-micromolar potencies against a panel of 4 solid tumor cell lines and 4 hematological cell lines with the most potent compound, 45h, having a cellular IC50 of 70 nM against the multiple myeloma cell line KMS-12-BM. Evidence of both JAK and HDAC pathway inhibition is presented in Hela cells showing that both pathways are modulated. Evidence of apoptosis with two compounds in 4 sold tumor cell lines is also presented. (C) 2018 Elsevier Masson SAS. All rights reserved.
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