Tag: 429.5175

Reduced state transition barrier of CDK6 from open to closed state induced by Thr177 phosphorylation and its implication in binding modes of inhibitors was written by He, Huan;Xu, Juan;Xie, Wen;Guo, Qing-Lian;Jiang, Feng-Lei;Liu, Yi. And the article was included in Biochimica et Biophysica Acta, General Subjects in 2018.Category: piperazines This article mentions the following:

CDK6 is considered as a highly validated anticancer drug target due to its essential role in regulating cell cycle progression at G1 restriction point. Activation of CDK6 requires the phosphorylation of Thr177 on A-loop, but the structural insights of the activation mechanism remain unclear. Herein, all-atoms mol. dynamics (MD) simulations were used to study the effects of Thr177 phosphorylation on the dynamic structure of CDK6-Vcyclin complex. MD results indicated that the free energy barrier of the transition from open to closed state decreased ∼ 47.2% after Thr177 phosphorylation. Key steps along the state transition process were obtained from a cluster anal. Binding preference of ten different inhibitors to open or closed state were also investigated through mol. docking along with MD simulations methods. Our results indicated that Thr177 phosphorylation increased the flexibility around the ATP-binding pocket. The transition of the ATP-binding pocket between open and closed states should be considered for understanding the binding of CDK6 inhibitors. This work could deepen the understanding of CDKs activation mechanism, and provide useful information for the discovery of new CDKs inhibitors with high affinity and specificity. In the experiment, the researchers used many compounds, for example, 8-Cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (cas: 1357470-29-1Category: piperazines).

8-Cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (cas: 1357470-29-1) belongs to piperazine derivatives. A form in which piperazine is commonly available industrially is as the hexahydrate, C4H10N2. 6H2O, which melts at 44 °C and boils at 125–130 °C. Piperazine is an anthelminthic especially useful in the treatment of partial intestinal obstruction caused by Ascaris worms, which is a condition primarily seen in children. Piperazine hydrate and piperazine citrate are the main anthelminthic piperazines.Category: piperazines

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models was written by Zhang, Xiaoping;Lv, Hua;Zhou, Qingyu;Elkholi, Rana;Chipuk, Jerry E.;Reddy, M. V. Ramana;Reddy, E. Premkumar;Gallo, James M.. And the article was included in Molecular Cancer Therapeutics in 2014.COA of Formula: C24H27N7O This article mentions the following:

ON123300 is a low mol. weight multikinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochem. assays indicated that ON123300 was a strong inhibitor of Ark5 and CDK4, as well as growth factor receptor tyrosine kinases such as β-type platelet-derived growth factor receptor (PDGFRβ). ON123300 inhibited U87 glioma cell proliferation with an IC₅₀ 3.4 ± 0.1 μmol/L and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation, both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K-initiated PI3K-neg. feedback loop. Cotreatment with the EGFR inhibitor gefitinib produced synergistic cytotoxic effects. Pursuant to the in vitro studies, in vivo pharmacokinetic and pharmacodynamic studies of ON123300 were completed in mice bearing intracerebral U87 tumors following i.v. doses of 5 and 25 mg/kg alone, and also at the higher dose concurrently with gefitinib. ON123300 showed high brain and brain tumor accumulation based on brain partition coefficient values of at least 2.5. Consistent with the in vitro studies, single agent ON123300 caused a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors, whereas addition of gefitinib to the ON123300 regimen significantly enhanced p-Akt inhibition and prevented Erk activation. In summary, ON123300 demonstrated favorable pharmacokinetic characteristics, and future development for brain tumor therapy would require use of combinations, such as gefitinib, that mitigate its Erk activation and enhance its activity. Mol Cancer Ther; 13(5); 1105-16. ©2014 AACR. In the experiment, the researchers used many compounds, for example, 8-Cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (cas: 1357470-29-1COA of Formula: C24H27N7O).

8-Cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (cas: 1357470-29-1) belongs to piperazine derivatives. Piperazine was first introduced as an anthelmintic in 1953. Piperazine compounds mediate their anthelmintic action by generally paralyzing parasites, allowing the host body to easily remove or expel the invading organism. Piperazine and its salts did not induce point mutations in a bacterial test. A series of mutagenicity studies in cells, both in vitro and in vivo, has been completed and showed no evidence of mutagenic effect.COA of Formula: C24H27N7O

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics