China
Africa
Explore chapters and articles related to this topic
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The protein mTOR (Mammalian Target of Rapamycin), also known as FRAP1 (FK506 Binding Protein 12-Rapamycin-Associated Protein 1), is encoded in humans by the FRAP1 gene. It is a serine/threonine protein kinase that regulates a number of cellular processes, including cell growth, proliferation, survival, motility, protein synthesis, and transcription. Belonging to the phosphatidylinositol 3-kinase-related kinase family, it is based at the centre of a complex regulatory network and works by sensing and integrating information from upstream pathways including energy levels, the presence of cellular nutrients (e.g., amino acids), insulin, and growth factors (such as IGF-1 and IGF-2), along with the redox status of the intracellular and extracellular environments. It transduces this information into directing the appropriate level of protein synthesis, cellular growth, and proliferation. The two best characterized molecular targets of mTORC1 signaling are p70-S6 kinase 1 (S6K1) and 4E-BP1, and the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (Figure 6.94). Details of the mTOR pathway.
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Finally, there are other cellular sensors/receptors that sense signals other than small molecules or the input from the nervous and endocrine systems. Such sensors measure stretch/length, tension/force, electrical potentials, and interactions with proteins and molecules on the surface of other cells. In the context of skeletal muscle, one example of such receptors is a class of proteins known as ‘mechanoreceptors’, with their sensory role currently being investigated as ‘mechanosensory’ regulation of signal transduction (also ‘mechanotransduction’), especially in the context of resistance exercise and the regulation of muscle protein synthesis MPS (12). The process of MPS and the marked increase in the rate of MPS during recovery from exercise, and its augmentation by the presence of aminoacidemia through protein ingestion, is considered to be central to inducing muscle hypertrophy in response to resistance exercise training (35). In other words, repeated transient increases in MPS through exercise and appropriate nutrition lead to the accumulation of myofibrillar proteins, and thereby increased size in the trained muscle (see Chapter 8). In the acute regulation of MPS, one example of mechanotransduction involves focal adhesion kinase (FAK) proteins, a class of transmembrane receptors that act as protein tyrosine kinases. FAK proteins are key elements for the transmission of contractile force through the skeletal muscle architecture, and thereby can also act as sensors of contractile activity. High force contraction can result in conformational changes and activation of FAK phosphotransferase activity, which activates MPS through mechanisms related to the mechanistic target of rapamycin complex (mTORC), ribosomal protein/p70 S6 kinase (S6K1) and several downstream pathways that can be both mTORC-dependent and -independent (12). For more details on mTORC and other potential mechanosensors for resistance exercise, see Chapter 8.
The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xinyuan Xu, Yingyi Chen, Qiang Fu, Duan Ni, Jian Zhang, Xiaolong Li, Shaoyong Lu
Phosphoinositide-dependent protein kinase-1 (PDK1) is a major regulator of the AGC family of kinases that phosphorylate and activate at least 23 related AGC protein kinases1, such as p70 S6 kinase (S6K)2,3, p90 ribosomal S6 kinase (RSK)4,5, serum and glucocorticoid-induced protein kinase (SGK)6,7, PKC isoforms8,9, protein kinase C-associated kinase 2 (PRK2)10, and PKB/AKT11–13. They can initiate tumorigenesis through the constitutive activation of kinases induced by oncogenic mutations14–16. Moreover, PDK1 plays a key role in the PI3K-AKT pathway, which is one of the most common deregulations in human cancers17–20. Thus, selective modulators of PDK1 may have utility as anti-cancer agents21–24.
Nobiletin prevents cadmium-induced neuronal apoptosis by inhibiting reactive oxygen species and modulating JNK/ERK1/2 and Akt/mTOR networks in rats
Published in Neurological Research, 2018
Youyang Qu, Yu Liu, Li Chen, Yanmei Zhu, Xingjun Xiao, Di Wang, Yulan Zhu
Akt/mTOR signaling pathway crucially involves in proliferation, differentiation, and cell survival [49,50]. mTOR phosphorylates and activates the eukaryotic initiation factor 4E binding protein (4EBP1) and ribosomal p70 S6 kinase (S6K1) that are important for down-stream of mTOR activity [26]. Expression of phosphorylated downstream targets p-4EBP1, p-S6K1, and mTOR were assessed. The expression of mTORc1 associated proteins raptor and mTORc2 associated protein, rictor were also assessed. Cd exposure was found to cause significant (p < 0.05) activation of the pathway as evidenced by up-regulations in the levels of raptor, rictor and p-S6K1 and p-4EBP1. The levels of Akt and p-Akt were also enhanced (Figure 4(a)–(c)). However, the expression of PTEN was slightly suppressed by Cd. Interestingly, nobiletin was found to block the phosphorylation of mTOR and, the expression of S6K1 and 4EBP1, as well the phosphorylated levels of S6K1 and 4EBP1 were reduced. The expression of raptor and rictor were also reduced while it enhanced PTEN expression. Down-regulated mTOR expression could have caused suppression of p-S6K1 and p-4EBP1. The observations indicate that nobiletin down-regulated Akt/mTOR signaling. Thus, inhibition of mTOR signaling by nobiletin could have also in part contributed to reduced neuronal apoptosis.
Rituximab (anti-CD20)-modified AZD-2014-encapsulated nanoparticles killing of B lymphoma cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Xiaolong Tang, Chunmei Xie, Zhenyou Jiang, Amin Li, Shiyu Cai, Changhao Hou, Jian Wang, Yong Liang, Dong Ma
The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is frequently dysregulated in B-cell non-Hodgkin’s lymphoma (NHL) cells. Hyperactivation of the pathway promotes tumorigenesis, tumor growth, invasion and metastasis [1,2]. Several mTOR-signaling components, including mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2), eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and p70-S6 kinase-1 (S6K) are highly expressed in most cancers [3,4]. Moreover, preclinical work has shown that inhibition of the PI3K/AKT/mTOR pathway was beneficial in the treatment of tumors [5]. mTOR inhibition resulted in decreased cancer-cell proliferation and downregulation of cellular survival in vitro and in vivo [6,7]. 3(2,4-Bis((S)-3-methylmorpholino) pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide (AZD-2014) is a novel and potent ATP-competitive mTOR inhibitor, which decreases p4EBP1 (Thr37/46), inhibits the translation initiation complex, and decreases overall protein synthesis to selectively block dual mTORC1 activation [8]. AZD-2014 also inhibits the mTORC2 biomarkers pAKTSer473 and pNDRG1Thr346 [9]. AZD-2014 has exhibited dose-dependent tumor-growth inhibition in several xenograft and primary explant models and has broad antiproliferative activity against various tumors [9,10]. Thus, the potential effects and underlying mechanism of AZD-2014 on NHL cell growth and survival deserve investigation. However, AZD-2014 non-specifically accumulates in healthy tissues and causes tissue damage [11,12]. Therefore, non-toxic, efficient AZD-2014 delivery systems for cancer treatment are needed [13].