期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 19, 页码 14540-14556出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01059
关键词
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资金
- Ascentage Pharma Group
- Rogel Cancer Center Support Grant from National Cancer Institute, NIH [P30 CA046592]
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
The discovery of exceptionally potent and efficacious EED inhibitors has demonstrated significant potential for the treatment of human cancers and other diseases. Through optimization and structural studies, a promising compound, EEDi-5273, has shown excellent inhibitory effects on tumor growth in experiments.
Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.
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