- Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure-Activity Relationship Analysis
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Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.
- Kant, Rajni,Yang, Ming-Hui,Tseng, Chih-Hua,Yen, Chia-Hung,Li, Wei-You,Tyan, Yu-Chang,Chen, Marcelo,Tzeng, Cherng-Chyi,Chen, Wei-Cheng,You, Kaiting,Wang, Wen-Chieh,Chen, Yeh-Long,Chen, Yi-Ming Arthur
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p. 8992 - 9009
(2021/07/19)
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- Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers
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Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kβ and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25 mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
- Barlaam, Bernard,Cosulich, Sabina,Delouvrié, Bénédicte,Ellston, Rebecca,Fitzek, Martina,Germain, Hervé,Green, Stephen,Hancox, Urs,Harris, Craig S.,Hudson, Kevin,Lambert-Van Der Brempt, Christine,Lebraud, Honorine,Magnien, Fran?oise,Lamorlette, Maryannick,Le Griffon, Antoine,Morgentin, Rémy,Ouvry, Gilles,Page, Ken,Pasquet, Georges,Polanska, Urszula,Ruston, Linette,Saleh, Twana,Vautier, Michel,Ward, Lara
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supporting information
p. 5155 - 5162
(2015/11/09)
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