Tag: 214.3046

A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2 was written by Martin-Gago, Pablo;Fansa, Eyad K.;Klein, Christian H.;Murarka, Sandip;Janning, Petra;Schuermann, Marc;Metz, Malte;Ismail, Shehab;Schultz-Fademrecht, Carsten;Baumann, Matthias;Bastiaens, Philippe I. H.;Wittinghofer, Alfred;Waldmann, Herbert. And the article was included in Angewandte Chemie, International Edition in 2017.Formula: C11H22N2O2 This article mentions the following:

Small-mol. inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (K_D<10 nM), interference with Ras signaling and growth inhibition require 5-20 μm compound concentrations We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas. In the experiment, the researchers used many compounds, for example, 1-Boc-4-(Aminomethyl)piperidine (cas: 144222-22-0Formula: C11H22N2O2).

1-Boc-4-(Aminomethyl)piperidine (cas: 144222-22-0) belongs to piperidine derivatives. The piperidine structural motif is present in numerous natural alkaloids. These include piperine, which gives black pepper its spicy taste. Industrially, piperidine is produced by the hydrogenation of pyridine, usually over a molybdenum disulfide catalyst. Pyridine can also be reduced to piperidine via a modified Birch reduction using sodium in ethanol.Formula: C11H22N2O2

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem

Design, synthesis and biological evaluation of pyridine derivatives as selective SHP2 inhibitors was written by Liu, Wen-Shan;Yang, Bing;Wang, Rui-Rui;Li, Wei-Ya;Ma, Yang-Chun;Zhou, Liang;Du, Shan;Ma, Ying;Wang, Run-Ling. And the article was included in Bioorganic Chemistry in 2020.Reference of 144222-22-0 This article mentions the following:

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which affects the transduction of multiple signaling pathways, including RAS-ERK, PI3K-AKT and JAK-STAT. SHP2 also plays an important role in the programmed cell death pathway (PD-1/PD-L1). Studies have shown that SHP2 is associated with a variety of cancers, including breast, liver and gastric cancers. Therefore, the development of SHP2 inhibitors has attracted extensive attention. In this study, based on the known inhibitor 1 (SHP099), novel SHP2 inhibitors were designed by means of scaffold hopping, and 35 pyridine derivatives as SHP2 inhibitors were found. The in vitro enzyme activity assay was performed on these compounds, and multiple selective SHP2 inhibitors with activity potency similar to that of SHP099 were obtained. Among them, compound (2-(4-(aminomethyl)piperidin-1-yl)-5-(2,3-dichlorophenyl)pyridin-3-yl)methanol (11a) was the most potent and highly selective SHP2 inhibitor with an in vitro enzyme activity IC₅₀ value of 1.36 μM. Fluorescence titration assay verified that 11a bound directly to SHP2 protein. Subsequently, cell assay of representative compounds showed that these compounds could effectively inhibit the proliferation of Ba/F₃ cells. In addition, the pharmacokinetic characteristics of the designed compounds were analyzed by the in silico ADMET prediction. Mol. docking study provided more detailed information on the binding mode of compounds and SHP2 protein. In brief, this study reported for the first time that pyridine derivatives as novel SHP2 inhibitors had good inhibitory activity and selectivity, providing new clues for the development of small mol. SHP2 inhibitors. In the experiment, the researchers used many compounds, for example, 1-Boc-4-(Aminomethyl)piperidine (cas: 144222-22-0Reference of 144222-22-0).

1-Boc-4-(Aminomethyl)piperidine (cas: 144222-22-0) belongs to piperidine derivatives. Piperidine is a metabolite of cadaverine, a polyamine found in the human intestine. The piperidine and polyhydroxylated indolizidine derivatives have shown to be promising α-glucosidase inhibitors. The former are analogs of DNJ with an improved α-glucosidase inhibitory profile than that of DNJ. Boisson et al.Reference of 144222-22-0

Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem