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Lin, Jian; Lu, Wei; Caravella, Justin A; Campbell, Ann Marie; Diebold, R. Bruce; Ericsson, Anna; Fritzen, Edward; Gustafson, Gary R; Lancia, David R; Shelekhin, Tatiana; Wang, Zhongguo; Castro, Jennifer; Clarke, Andrea; Gotur, Deepali; Josephine, Helen R; Katz, Marie; Diep, Hien; Kershaw, Mark; Yao, Lili; Kauffman, Goss; Hubbs, Stephen E; Luke, George P; Toms, Angela V; Wang, Liann; Bair, Kenneth W; Barr, Kenneth J; Dinsmore, Christopher; Walker, Duncan; Ashwell, Susan
Journal of medicinal chemistry, 07/2019, Letnik: 62, Številka: 14Journal Article
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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