1232836-35-9Relevant academic research and scientific papers
Discovery of type II inhibitors of tgfβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)
Tan, Li,Nomanbhoy, Tyzoon,Gurbani, Deepak,Patricelli, Matthew,Hunter, John,Geng, Jiefei,Herhaus, Lina,Zhang, Jianming,Pauls, Eduardo,Ham, Youngjin,Choi, Hwan Geun,Xie, Ting,Deng, Xianming,Buhrlage, Sara J.,Sim, Taebo,Cohen, Philip,Sapkota, Gopal,Westover, Kenneth D.,Gray, Nathanael S.
, p. 183 - 196 (2015/03/04)
We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,
PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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Page/Page column 48; 49, (2014/12/12)
The present invention relates to 6-amino-7-deaza-purine derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present
Broad spectrum alkynyl inhibitors of T315I Bcr-Abl
Deng, Xianming,Lim, Sang Min,Zhang, Jianming,Gray, Nathanael S.
scheme or table, p. 4196 - 4200 (2010/08/22)
A series of alkyne-containing type II inhibitors with potent inhibitory activity of T315I Bcr-Abl has been identified. The most active compound 4 exhibits an EC50 of less than 1 nM against wild-type Bcr-Abl and an EC50 of 10 nM again
Discovery of 3-[2-(imidazo[1,2- b ]pyridazin-3-yl)ethynyl]-4-methyl- N -{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant
Huang, Wei-Sheng,Metcalf, Chester A.,Sundaramoorthi, Raji,Wang, Yihan,Zou, Dong,Thomas, R. Mathew,Zhu, Xiaotian,Cai, Lisi,Wen, David,Liu, Shuangying,Romero, Jan,Qi, Jiwei,Chen, Ingrid,Banda, Geetha,Lentini, Scott P.,Das, Sasmita,Xu, Qihong,Keats, Jeff,Wang, Frank,Wardwell, Scott,Ning, Yaoyu,Snodgrass, Joseph T.,Broudy, Marc I.,Russian, Karin,Zhou, Tianjun,Commodore, Lois,Narasimhan, Narayana I.,Mohemmad, Qurish K.,Iuliucci, John,Rivera, Victor M.,Dalgarno, David C.,Sawyer, Tomi K.,Clackson, Tim,Shakespeare, William C.
experimental part, p. 4701 - 4719 (2010/10/03)
In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC 50s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABLT315I expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.
