期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02242-4
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资金
- NIH
- FAMRI foundation
- V foundation
- Rete Ematologica Lombarda (FRRB Regione Lombardia)
- Italian Association for Cancer Research [IG15208, IG19162]
- PRIN [20152TE5PK]
- NIH [R01GM114306]
- EMBO ALTF [261-2011]
- Wellcome Trust [WT100237]
- Biotechnology and Biological Sciences Research Council [BB/J009598/1]
- 4SC
- Cancer Research UK [C20953/A18644]
- Biotechnology and Biological Sciences Research Council Project [BB/L01923X/1]
- British Skin Foundation Project [7015]
- Royal Society Wolfson Research Merit Award
- BBSRC [BB/N002954/1] Funding Source: UKRI
- NATIONAL CANCER INSTITUTE [R01CA074305, R01CA212639] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007445, R01GM114306, R37GM062437, R01GM078221] Funding Source: NIH RePORTER
- Biotechnology and Biological Sciences Research Council [BB/N002954/1] Funding Source: researchfish
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin's favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities.
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