- Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach
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Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.
- Chen, Chao,Zhu, Hugh,Stauffer, Frédéric,Caravatti, Giorgio,Vollmer, Susanne,Machauer, Rainer,Holzer, Philipp,M?bitz, Henrik,Scheufler, Clemens,Klumpp, Martin,Tiedt, Ralph,Beyer, Kim S.,Calkins, Keith,Guthy, Daniel,Kiffe, Michael,Zhang, Jeff,Gaul, Christoph
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- Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR
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The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.
- Yu, Tao,Li, Ning,Wu, Chengde,Guan, Amy,Li, Yi,Peng, Zhengang,He, Miao,Li, Jie,Gong, Zhen,Huang, Lei,Gao, Bo,Hao, Dongling,Sun, Jikui,Pan, Yan,Shen, Liang,Chan, Chichung,Lu, Xiulian,Yuan, Hongyu,Li, Yongguo,Li, Jian,Chen, Shuhui
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p. 256 - 261
(2018/03/21)
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
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The present invention provides compounds of formula I: [INSERT FORMULA HERE] or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, such as malaria.
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Page/Page column 165
(2014/06/11)
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- PI3K/M TOR INHIBITORS
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The invention relates to PI3K/mTOR inhibiting compounds consisting of the formula (I): wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; meth
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Page/Page column 143-144
(2010/04/03)
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- Inhibitors of PI3 kinase
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The present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, that inhibit phosphoinositide 3-kinase; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds.
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Page/Page column 37-38
(2009/07/10)
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- INHIBITORS OF PI3 KINASE
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The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds, wherein Q, X1, X2, R1 and Z are as defined herein.
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Page/Page column 96-97
(2010/01/12)
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- INDOLE DERIVATIVES
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The invention concerns indole derivatives of Formula (I) or pharmaceutically-acceptable salts thereof, wherein each of Ring A, m, R1, R2, n, R3 and G1 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of disease mediated by a PI3K enzyme and/or a mTOR kinase.
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Page/Page column 87-88
(2008/06/13)
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