Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 15, Pages 6546-6573Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01925
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Funding
- Foundation for Applied Medical Research (FIMA)
- University of Navarra (Pamplona, Spain)
- Asociacion de Amigos of the University of Navarra
- Fundacion Fuentes Dutor
- Ministerio de Economia y Competitividad
- Instituto de Salud Carlos III (FEDER funds) [PI10/01691, PI13/00862, PI13/01469, PI14/01867, PI16/02024, RTICC RD12/0036/0068, CIBERONC (CB16/12/00489)]
- ERA-NET programs TRANSCAN-2 JTC EPICA by the Torres Quevedo Subprogram [PTQ-11-04777, PTQ-14-07320 I.D.M]
- Fundacio La Marato de TV3 [20132130-31-32]
- Gobierno de Navarra [40/2016, PT053/2016, PT027/2017]
- FSE (Inncorpora-Torres Quevedo grant)
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Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, molecules bearing a 4-aminoquinoline scaffold were reported as dual inhibitors of these targets and showed a significant in vivo efficacy in animal models of hematological malignancies. Here, we report a detailed exploration around three growing vectors born by this chemotype. Exploring this chemical space led to the identification of features to navigate G9a and DNMT1 biological spaces: not only their corresponding exclusive areas, selective compounds, but also common spaces. Thus, we identified from selective G9a and first-in-class DNMT1 inhibitors, >1 log unit between their IC50 values, with IC50 < 25 nM (e.g., 43 and 26, respectively) to equipotent inhibitors with IC50 < 50 nM for both targets (e.g., 13). Their ADME/Tox profiling and antiproliferative efficacies, versus some cancer cell lines, are also reported.
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