Many of the cellular processes

Many of the cellular processes regulated by AKT activation are also controlled by other intracellular pathways such as the MAPK pathway, the PLCγ pathway, but also, directly or indirectly, by signaling pathways not linked to RTK transmembrane receptors, such as growth factor-linked signaling affecting important steps of neural crest formation, e.g. BMPs or Wnt signals. The complex crosstalk between pathways, its temporal, spatial and cell-type specificity, as well as the importance of the temporal dynamics of each signal, are emerging as key parameters necessary to elicit the appropriate response in each cell context (Ciarlo et al., 2017, Vasudevan et al., 2015). Additional modulation of AKT activation by posttranslational modifications, redundancy or specific roles for each member of the families of kinases, phosphatases, and other AZD2858 australia involved in AKT modifications, adds a further layer of biological complexity to the matter. Altogether, the recent involvement of AKT signaling at all the steps of neural crest formation for multiple responses, including early patterning events which were thought to rely mainly on transcriptional regulation, implicate this pathway as an integral partner of the NC-GRN in future studies.
Acknowledgements and funding The authors are very grateful to Dr. K. Liu and P. Scerbo for their critical reading of the manuscript, and to all members of the Monsoro-Burq team for interactive discussions. This study was supported by funding from Université Paris Sud, Centre National de la Recherche Scientifique (CNRS), Agence Nationale pour la Recherche (ANR Programme Blanc CrestNetMetabo: ANR-15-CE13-0012-01-CRESTNETMETABO), and Fondation pour la Recherche Médicale (FRM, Programme Equipes Labellisées DEQ20150331733) and Institut Universitaire de France to AHMB. M.S. is a Ph.D. fellow funded by Fondation pour la Recherche Médicale (ECO20160736105).
AKT, also known as protein kinase B (PKB), is a serine-threonine protein kinase that plays a key role in the phosphotidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Increased AKT activation has been implicated in a wide variety of cancers. AKT is identified in three forms with distinct biological relevance: AKT1 is ubiquitously expressed and is the isoform that is believed to play a key role in cancer; AKT2 is highly expressed in muscle, liver and adipocytes and contributes to cell motility and invasion; AKT3 is predominately overexpressed in certain breast, glioma and prostate tumors., , Based on these factors, many efforts to identify AKT inhibitors with acceptable pharmaceutical properties have been pursued. However, the discovery of AKT inhibitors having AGC kinase family selectivity has posed a significant challenge due to high homology in the adenosine triphosphate (ATP) binding pocket among the AGC kinase family members. The kinase selectivity over ROCK2 is important since it’s another member of the AGC kinase family and is involved in regulation of vascular tone and thus control of blood pressure. There is high homology within the AGC kinase family, with AKT1 and ROCK2 sharing 86% sequence identity (100% similarity) when the 15 residues within 3 Å of ATP pocket are considered. Several compounds with varying levels of AKT selectivity have been identified, but only a limited number of chemotypes have been reported to have entered early phase clinical trials, including the orally bioavailable dihyrocyclopentapyrimidine (GDC-0068) and triazolopyrimidine an allosteric AKT inhibitor (MK-2206) (). We recently described the development of selective p70S6K inhibitor (LY-2584702) and AKT-p70S6K dual inhibitor (LY-2780301) for treatment of advanced solid tumors,, we also have pursued development of selective AKT inhibitors for this indication. Here we report for the first time the identification of novel chiral DHP as potent AKT inhibitors with high selectivity for AGC family kinases. Our initial approach was focused on optimizing the hinge binding bicyclic moiety of the inhibitor for selectivity and potency optimization, and then turned our attention to the -alkyl substitution of the imidazole towards optimizing the physicochemical property of our hit series by replacing the aryl-heteroaryl bond with less lipophilic aliphatic substitutions that led to improved aqueous solubility and druglike properties as shown in .