Efficient synthesis of novel disubstituted pyrido[3,4-b]pyrazines for the design of protein kinase inhibitors

MedChemComm ◽  
2016 ◽  
Vol 7 (2) ◽  
pp. 224-229 ◽  
Author(s):  
Maud Antoine ◽  
Tilmann Schuster ◽  
Irene Seipelt ◽  
Babette Aicher ◽  
Michael Teifel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Related Protein ◽  
Efficient Synthesis ◽  
Aniline Derivatives

Urea and aniline derivatives were active at low micromomolar IC50 values against a panel of seven cancer-related protein kinases.

Release of dopamine and norepinephrine by hypoxia from PC-12 cells

1998 ◽  
Vol 274 (6) ◽  
pp. C1592-C1600 ◽  
Author(s):  
Ganesh K. Kumar ◽  
Jeffrey L. Overholt ◽  
Gary R. Bright ◽  
Kwong Y. Hui ◽  
Hongwen Lu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Culture Conditions ◽  
Protein Kinase Inhibitors ◽  
Channel Blockers ◽  
Pc 12 Cells ◽  
Stimulus Secretion Coupling ◽  
Carbon Fiber Electrode ◽  
Da Release

We examined the effects of hypoxia on the release of dopamine (DA) and norepinephrine (NE) from rat pheochromocytoma 12 (PC-12) cells and assessed the involvement of Ca2+ and protein kinases in stimulus-secretion coupling. Catecholamine release was monitored by microvoltammetry using a carbon fiber electrode as well as by HPLC coupled with electrochemical detection (ECD). Microvoltammetric analysis showed that hypoxia-induced catecholamine secretion (Po 2 of medium ∼40 mmHg) occurred within 1 min after the onset of the stimulus and reached a plateau between 10 and 15 min. HPLC-ECD analysis revealed that, at any level of Po 2, the release of NE was greater than the release of DA. In contrast, in response to K+ (80 mM), DA release was ∼11-fold greater than NE release. The magnitude of hypoxia-induced NE and DA releases depended on the passage, source, and culture conditions of the PC-12 cells. Omission of extracellular Ca2+ or addition of voltage-gated Ca2+ channel blockers attenuated hypoxia-induced release of both DA and NE to a similar extent. Protein kinase inhibitors, staurosporine (200 nM) and bisindolylmaleimide I (2 μM), on the other hand, attenuated hypoxia-induced NE release more than DA release. However, protein kinase inhibitors had no significant effect on K+-induced NE and DA releases. These results demonstrate that hypoxia releases catecholamines from PC-12 cells and that, for a given change in Po 2, NE release is greater than DA release. It is suggested that protein kinases are involved in the enhanced release of NE during hypoxia.

scholarly journals Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3226 ◽  
Author(s):  
Colin Bournez ◽  
Fabrice Carles ◽  
Gautier Peyrat ◽  
Samia Aci-Sèche ◽  
Stéphane Bourg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chemical Space ◽  
Principal Component ◽  
Great Majority ◽  
Protein Kinase Inhibitors ◽  
Principal Moments Of Inertia

Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of “flatland”, we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website: http://www.icoa.fr/pkidb.

Targeting Protein Kinase Inhibitors with Traditional Chinese Medicine

2019 ◽  
Vol 20 (15) ◽  
pp. 1505-1516
Author(s):  
Yangyang Zhang ◽  
Minghua Liu ◽  
Jun Wang ◽  
Jianlin Huang ◽  
Mingyue Guo ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Protein Kinase ◽  
Traditional Chinese Medicine ◽  
Protein Kinases ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Specific Protein ◽  
Protein Kinase Inhibitors ◽  
Bioactive Substances ◽  
Phosphoinositide 3 Kinase

Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.

Protein kinase-independent inhibition of muscarinic K+ channels by staurosporine

1994 ◽  
Vol 266 (4) ◽  
pp. C1128-C1132 ◽  
Author(s):  
C. F. Lo ◽  
G. E. Breitwieser
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Single Channel ◽  
Protein Kinase Inhibitors ◽  
K Channel ◽  
K Current ◽  
Excised Patches ◽  
Dose Dependent Decrease ◽  
Gamma S

Acetylcholine (ACh) binding to atrial muscarinic receptors activates an inwardly rectifying K+ current (IK[ACh]) via a pertussis toxin-sensitive GTP-binding protein (GK). The muscarinic K+ channel (termed GIRK1) has been cloned, and the nucleotide sequence contains nine consensus sites for protein kinase C (PKC) phosphorylation (16). Dephosphorylation of the muscarinic K+ channel has been implicated in rapid IK[ACh] desensitization in the presence of agonist (13). Staurosporine is a widely used membrane-permeant inhibitor of PKC and other protein kinases (7), including G protein-coupled receptor kinases. We investigated the role of phosphorylation in the regulation of IK[ACh] by examining the effect of a variety of protein kinase inhibitors. Staurosporine produced a rapid and reversible dose-dependent decrease in IK[ACh], activated by either GTP or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). Other PKC inhibitors, including calphostin C and K-252b, were without effect on GTP gamma S-activated IK[ACh]. In excised patches of atrial membrane under nonphosphorylating conditions (0 ATP, 1 mM 5'-adenylylimidodiphosphate), staurosporine reversibly reduced muscarinic K+ channel activity without altering single-channel current amplitude. These results suggest that staurosporine inhibits IK[ACh] by a mechanism independent of intracellular protein kinases.

scholarly journals Novel Protein Kinase Induced during Sporangial Cleavage in the Oomycete Phytophthora infestans

2002 ◽  
Vol 1 (5) ◽  
pp. 687-695 ◽  
Author(s):  
Howard S. Judelson ◽  
Samuel Roberts
Keyword(s):  
Protein Kinase ◽  
Phytophthora Infestans ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Protein Kinase Inhibitors ◽  
Kinase Gene ◽  
Mrna Accumulation ◽  
Calmodulin Antagonist ◽  
Zoospore Release

ABSTRACT A study of the effect of inhibitors on zoospore development in Phytophthora infestans demonstrated the involvement of protein kinases and calcium and led to the discovery of a gene induced during zoosporogenesis that encoded a protein resembling Ca+2- and calmodulin-regulated serine/threonine protein kinases. The calcium channel blocker verapamil and the calmodulin antagonist trifluoroperazine inhibited zoosporogenesis and encystment. The protein kinase inhibitors K-252a and KN-93 inhibited zoospore release, encystment, and cyst germination, and K-252a reduced zoospore viability. In contrast, the inhibitors had minor or no effects on sporangia directly germinating in media. Spurred by these findings, a survey of putative protein kinase genes was performed to identify any that were up-regulated during zoosporogenesis. A kinase-encoding gene was identified for which mRNA accumulation was first detected soon after chilling sporangia in water, conditions that induce sporangial cytoplasm to cleave and release zoospores. The transcript persisted in motile zoospores and in germinated cysts but was not detected in other tissues, including hyphae, hyphae placed in water, or directly germinating sporangia. The structure of the predicted protein was novel, as its C-terminal region, which binds calmodulin in related proteins, was unusually short. Concentrations of actinomycin D previously used in experiments that suggested that de novo transcription was not needed for zoosporogenesis or encystment only partially inhibited transcription of the kinase gene, probably due to poor uptake into sporangia.

scholarly journals Targeting the trypanosome kinetochore with CLK1 protein kinase inhibitors

2019 ◽  
Author(s):  
Manuel Saldivia ◽  
Srinivasa P.S. Rao ◽  
Eric Fang ◽  
Elmarie Myburgh ◽  
Elaine Brown ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Competitive Inhibition ◽  
Binding Pocket ◽  
Protein Kinase Inhibitors ◽  
Kinetochore Assembly ◽  
Phenotypic Screen ◽  
Novel Drug

ABSTRACTThe kinetochore is a macromolecular structure that assembles on the centromeres of chromosomes and provides the major attachment point for spindle microtubules during mitosis. In Trypanosoma brucei the proteins that make up the kinetochore are highly divergent, with the inner kinetochore comprising at least 20 distinct and essential proteins (KKT1-20) that include four protein kinases, CLK1 (KKT10), CLK2 (KKT19), KKT2 and KKT3. We performed a phenotypic screen of T. brucei bloodstream forms with a Novartis kinase-focused inhibitor library, which identified a number of selective inhibitors with potent pan-kinetoplastid activity. Deconvolution of an amidobenzimidazole series using a selection of 37 T. brucei mutants that over-express known essential protein kinases identified CLK1 as the primary target. Biochemical studies show that the irreversible competitive inhibition of CLK1 is dependent on a Michael acceptor forming an irreversible bond with C215 in the ATP binding pocket, a residue that is not present in human CLK1, thereby providing selectivity. Chemical inhibition of CLK1 impairs inner kinetochore recruitment and compromises cell cycle progression, leading to cell death. We show that KKT2 is a substrate for CLK1 and identify phosphorylation of S508 to be essential for KKT2 function and for kinetochore assembly. We propose that CLK1 is part of a novel signalling cascade that controls kinetochore function via phosphorylation of the inner kinetochore protein kinase KKT2. This work highlights a novel drug target for trypanosomatid parasitic protozoa and a new chemical tool for investigating the function of their divergent kinetochores.

scholarly journals Importance of Protein Kinase and Its Inhibitor: A Review

2021 ◽  
Author(s):  
Panneerselvam Theivendren ◽  
Selvaraj Kunjiappan ◽  
Yashoda Mariappa Hegde ◽  
Sivakumar Vellaichamy ◽  
Murugananthan Gopal ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Information Transfer ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Growth Factor Receptors ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein ◽  
Regulate Cell Growth

Deregulation of a broad range of protein kinases has been linked to the development and growth of cancer cells. Protein kinases are intracellular enzymes that regulate cell growth and proliferation as well as the triggering and regulation of immune responses. Protein kinases are important therapeutic targets in cancer because of their critical role in signalling mechanisms that drive malignant cell characteristics. Intensive efforts in drug research have been made in this area over the last two decades. The current study delves into the catalytic domain of a protein kinase as well as information transfer from the cell’s membrane to internal targets. It also discusses the function of protein kinases in signal transduction and their cellular signalling pathways. Furthermore, it specifically outlines a systematic method to hybrid therapies to solve the issue of protein kinase resistance. The therapeutic use of nitric oxide, as well as other targets such as Phosphoinositide 3-kinases (PI3K), Protein Kinase B (Akt), serine/threonine protein kinase (mTOR), p38 mitogen-activated protein kinases (p38 MAPK), vascular endothelial growth factor receptors (VEGFR), epidermal growth factor receptors (EGFR), and anaplastic lymphoma (ALK) etc., According to the review article, selective therapy has shown high effectiveness in the treatment of advanced cancer, with protein kinase inhibitors being a main focus of the therapy. As a result, the latest review summarized that, the current state of science with the aim of identifying a novel protein kinase inhibitor that may be utilized in the treatment of advanced cancers.

scholarly journals The specificities of protein kinase inhibitors: an update

2003 ◽  
Vol 371 (1) ◽  
pp. 199-204 ◽  
Author(s):  
Jenny BAIN ◽  
Hilary McLAUCHLAN ◽  
Matthew ELLIOTT ◽  
Philip COHEN
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Glycogen Synthase ◽  
Specific Protein ◽  
Protein Kinase Inhibitors ◽  
Glycogen Synthase Kinase 3 ◽  
Dual Specificity ◽  
Combined Use ◽  
Dependent Protein

We have previously examined the specificities of 28 commercially available compounds, reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases [Davies, Reddy, Caivano and Cohen (2000) Biochem. J. 351, 95—105]. In the present study, we have extended this analysis to a further 14 compounds. Of these, indirubin-3′-monoxime, SP 600125, KT 5823 and ML-9 were found to inhibit a number of protein kinases and conclusions drawn from their use in cell-based assays are likely to be erroneous. Kenpaullone, Alsterpaullone, Purvalanol, Roscovitine, pyrazolopyrimidine 1 (PP1), PP2 and ML-7 were more specific, but still inhibited two or more protein kinases with similar potency. Our results suggest that the combined use of Roscovitine and Kenpaullone may be useful for identifying substrates and physiological roles of cyclin-dependent protein kinases, whereas the combined use of Kenpaullone and LiCl may be useful for identifying substrates and physiological roles of glycogen synthase kinase 3. The combined use of SU 6656 and either PP1 or PP2 may be useful for identifying substrates of Src family members. Epigallocatechin 3-gallate, one of the main polyphenolic constituents of tea, inhibited two of the 28 protein kinases in the panel, dual-specificity, tyrosine-phosphorylated and regulated kinase 1A (DYRK1A; IC50 = 0.33μM) and p38-regulated/activated kinase (PRAK; IC50 = 1.0μM).

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