Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 4, Pages 1580-1598Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01527
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Funding
- Searle Scholar award
- V Foundation
- UCSF Prostate Cancer Developmental Research Program
- Arthritis Research UK [20522]
- NIHR Oxford Biomedical Research Unit
- Rosetrees Trust
- Abbvie
- Bayer Healthcare
- Boehringer Ingelheirn
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Eli Lilly and Company
- Genome Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Janssen
- Novartis Research Foundation
- Pfizer
- Takeda
- Wellcome Trust
- [GM59957]
- [GM71630]
- Engineering and Physical Sciences Research Council [1100667] Funding Source: researchfish
- Rosetrees Trust [M289-F1, M289] Funding Source: researchfish
- Versus Arthritis [20522] Funding Source: researchfish
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Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PD CA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600 000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by similar to 3 log-orders to yield compound 35 (K-i = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDMS subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
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