65996-50-1Relevant articles and documents
Thermodynamic analysis of mRNA cap binding by the human initiation factor eIF4E via free energy perturbations
Guimaraes, Cristiano R. W.,Kopecky, David J.,Mihalic, Jeff,Shen, Shanling,Jeffries, Shawn,Thibault, Stephen T.,Chen, Xiaoqi,Walker, Nigel,Cardozo, Mario
, p. 18139 - 18146 (2009)
Eukaryotic mRNAs are appended at the 5′ end, with the 7-methylguanosine cap linked by a 5′-5′-triphosphate bridge to the first transcribed nucleoside (m7GpppX). Initiation of cap-dependent translation of mRNA requires direct interaction between the cap st
Anticancer Properties of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity via N5 Substitution
Cawrse, Brian M.,Lapidus, Rena S.,Cooper, Brandon,Choi, Eun Yong,Seley-Radtke, Katherine L.
, p. 178 - 185 (2017/12/26)
Halogenated pyrrolo[3,2-d]pyrimidine analogues have shown antiproliferative activity in recent studies, with cell accumulation occurring in the G2/M stage without apoptosis. However, the mechanism of action and pharmacokinetic (PK) profile of these compounds has yet to be determined. To investigate the PK profile of these compounds, a series of halogenated pyrrolo[3,2-d]pyrimidine compounds was synthesized and first tested for activity in various cancer cell lines followed by a mouse model. EC50 values ranged from 0.014 to 14.5 μm, and maximum tolerated doses (MTD) in mice were between 5 and 10 mg kg?1. This indicates a wide variance in activity and toxicity that necessitates further study. To decrease toxicity, a second series of compounds was synthesized with N5-alkyl substitutions in an effort to slow the rate of metabolism, which was thought to be leading to the toxicity. The N-substituted compounds demonstrated comparable cell line activity (EC50 values between 0.83–7.3 μm) with significantly decreased toxicity (MTD=40 mg kg?1). Finally, the PK profile of the active N5-substituted compound shows a plasma half-life of 32.7 minutes, and rapid conversion into the parent unsubstituted analogue. Together, these data indicate that halogenated pyrrolo[3,2-d]pyrimidines present a promising lead into potent antiproliferative agents with tunable activity and toxicity, and rapid metabolism.
INHIBITORS OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE
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Paragraph 00473, (2017/12/29)
Disclosed herein are inhibitors of IRAK protein kinase. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the IRAK inhibitors are described, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.