41381-89-9Relevant articles and documents
Discovery and Optimization of 2 H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer
Rohde, Jason M.,Karavadhi, Surendra,Pragani, Rajan,Liu, Li,Fang, Yuhong,Zhang, Weihe,McIver, Andrew,Zheng, Hongchao,Liu, Qingyang,Davis, Mindy I.,Urban, Daniel J.,Lee, Tobie D.,Cheff, Dorian M.,Hollingshead, Melinda,Henderson, Mark J.,Martinez, Natalia J.,Brimacombe, Kyle R.,Yasgar, Adam,Zhao, Wei,Klumpp-Thomas, Carleen,Michael, Sam,Covey, Joseph,Moore, William J.,Stott, Gordon M.,Li, Zhuyin,Simeonov, Anton,Jadhav, Ajit,Frye, Stephen,Hall, Matthew D.,Shen, Min,Wang, Xiaodong,Patnaik, Samarjit,Boxer, Matthew B.
, p. 4913 - 4946 (2021/05/07)
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
COMPOUNDS FOR THE MODULATION OF MYC ACTIVITY
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Paragraph 0152; 0153; 0154, (2019/02/24)
The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.
New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold
Pajk, Stane,?ivec, Matej,?ink, Roman,Sosi?, Izidor,Neu, Margarete,Chung, Chun-Wa,Martínez-Hoyos, María,Pérez-Herrán, Esther,álvarez-Gómez, Daniel,álvarez-Ruíz, Emilio,Mendoza-Losana, Alfonso,Castro-Pichel, Julia,Barros, David,Ballell-Pages, Lluís,Young, Robert J.,Convery, Maire A.,Encinas, Lourdes,Gobec, Stanislav
supporting information, p. 252 - 257 (2016/05/02)
Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.