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Science Signaling Mar 2016Despite the efforts of pharmaceutical companies to develop specific kinase modulators, few drugs targeting kinases have been completely successful in the clinic. This is... (Review)
Review
Despite the efforts of pharmaceutical companies to develop specific kinase modulators, few drugs targeting kinases have been completely successful in the clinic. This is primarily due to the conserved nature of kinases, especially in the catalytic domains. Consequently, many currently available inhibitors lack sufficient selectivity for effective clinical application. Kinases phosphorylate their substrates to modulate their activity. One of the important steps in the catalytic reaction of protein phosphorylation is the correct positioning of the target residue within the catalytic site. This positioning is mediated by several regions in the substrate binding site, which is typically a shallow crevice that has critical subpockets that anchor and orient the substrate. The structural characterization of this protein-protein interaction can aid in the elucidation of the roles of distinct kinases in different cellular processes, the identification of substrates, and the development of specific inhibitors. Because the region of the substrate that is recognized by the kinase can be part of a linear consensus motif or a nonlinear motif, advances in technology beyond simple linear sequence scanning for consensus motifs were needed. Cost-effective bioinformatics tools are already frequently used to predict kinase-substrate interactions for linear consensus motifs, and new tools based on the structural data of these interactions improve the accuracy of these predictions and enable the identification of phosphorylation sites within nonlinear motifs. In this Review, we revisit kinase-substrate interactions and discuss the various approaches that can be used to identify them and analyze their binding structures for targeted drug development.
Topics: Amino Acid Motifs; Animals; Computational Biology; Drug Delivery Systems; Humans; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship; Substrate Specificity
PubMed: 27016527
DOI: 10.1126/scisignal.aad4016 -
Drug Discovery Today. Technologies Nov 2015Protein kinases have become one of the most intensively pursued classes of drug targets for many diseases such as cancers and inflammatory diseases. Kinase profiling... (Review)
Review
Protein kinases have become one of the most intensively pursued classes of drug targets for many diseases such as cancers and inflammatory diseases. Kinase profiling work seeks to understand general selectivity trends of lead compounds across the kinome, which help with target selection, compound prioritization, and potential implications in toxicity. Under the current drug discovery process, screening of compounds against comprehensive panels of kinases and their mutants has become the standard approach. Many screening assays and technologies which are compatible for high-throughput screening (HTS) against kinases have been extensively pursued and developed.
Topics: Drug Discovery; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Technology, Pharmaceutical
PubMed: 26723886
DOI: 10.1016/j.ddtec.2015.10.007 -
Current Pharmaceutical Design Nov 2017Over the last three decades, neoplasms have become the largest cause of human mortality due to both high tumor incidence and mortality. Chemotherapy is one of the main... (Review)
Review
Over the last three decades, neoplasms have become the largest cause of human mortality due to both high tumor incidence and mortality. Chemotherapy is one of the main therapies employed to treat neoplasms. Although classical genotoxic drugs, such as cyclophosphamide, 5-FU, cisplatin and doxorubicin have been applied in clinical settings and have achieved very good treatment efficacy, many cancer patients died of tumor metastasis, drug toxicity or drug resistance due to tumor heterogeneity. Targeted molecular treatments based on the genes, receptors, and kinases expressed by a tumor make individualized treatment possible. Protein kinases catalyze the phosphorylation of proteins and are involved in multiple cellular processes. In many cancers, mutation or abnormal expression of protein kinases is correlated with tumorigenesis, metastasis and resistance to chemotherapy. Tumor-related protein kinases have become important molecular targets and biomarkers. The use of protein kinases as tumor biomarkers primarily focuses on tyrosine and serine/threonine kinases. Many tumor drugs targeting protein kinases, such as monoclonal antibody and tyrosine kinase inhibitors (TKIs), are widely utilized in clinic. Additional drugs aimed at combating drug resistance and metastasis should be developed targeting protein kinases. In this review, we summarize several important protein kinases involved in cancer and analyze why these kinases can be used as biomarkers or targets for cancer diagnosis and/or treatment. Furthermore, numerous drugs targeting protein kinases as well as their development and activity are discussed.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Humans; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 28730960
DOI: 10.2174/1381612823666170720113216 -
Autophagy Feb 2022The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon...
The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon stress-induced mitophagy that is largely regulated by the E3 ligase PRKN, with limited insight into the mechanisms regulating basal "housekeeping" mitophagy levels in different model organisms. Using iron chelation as an inducer of PRKN-independent mitophagy, we recently screened an siRNA library of lipid-binding proteins and determined that two kinases, GAK and PRKCD, act as positive regulators of PRKN-independent mitophagy. We demonstrate that PRKCD is localized to mitochondria and regulates recruitment of ULK1-ATG13 upon induction of mitophagy. GAK activity, by contrast, modifies the mitochondrial network and lysosomal morphology that compromise efficient transport of mitochondria for degradation. Impairment of either kinase blocks basal mitophagy, demonstrating the biological relevance of our findings. CCCP: carbonyl cyanide-m-chlorophenyl hydrazone; DFP: deferiprone; GAK: cyclin G associated kinase; HIF1A: hypoxia inducible factor 1 subunit alpha; PRKC/PKC: protein kinase C; PRKCD: protein kinase C delta; PRKN: parkin RBR E3 ubiquitin protein ligase.
Topics: Autophagy; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Mitophagy; Protein Kinase C-delta; Protein Kinases; Ubiquitin-Protein Ligases
PubMed: 35001811
DOI: 10.1080/15548627.2021.2015154 -
Drug Research Apr 2023Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of... (Review)
Review
Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of genes in the genome, which encode for all the protein kinases. Certain mutations in the kinome have been linked to dysregulation of protein kinases, which in turn can lead to several diseases and disorders including cancer. In this review, we have briefly discussed the role of protein kinases in various biochemical processes by categorizing cancer associated phenotypes and giving their protein kinase examples. Various techniques have also been discussed, which are being used to analyze the structure of protein kinases, and associate their roles in the oncogenesis. We have also discussed protein kinase inhibitors and United States Federal Drug Administration (USFDA) approved drugs, which target protein kinases and can serve as a counter to protein kinase dysregulation and mitigate the effects of oncogenesis. Overall, this review briefs about the importance of protein kinases, their roles in oncogenesis on dysregulation and how their inhibition via various drugs can be used to mitigate their effects.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Neoplasms; Carcinogenesis
PubMed: 36822216
DOI: 10.1055/a-1989-1856 -
Plant Communications Jan 2022Reproduction is a crucial process in the life span of flowering plants, and directly affects human basic requirements in agriculture, such as grain yield and quality.... (Review)
Review
Reproduction is a crucial process in the life span of flowering plants, and directly affects human basic requirements in agriculture, such as grain yield and quality. Typical receptor-like protein kinases (RLKs) are a large family of membrane proteins sensing extracellular signals to regulate plant growth, development, and stress responses. In and other plant species, RLK-mediated signaling pathways play essential roles in regulating the reproductive process by sensing different ligand signals. Molecular understanding of the reproductive process is vital from the perspective of controlling male and female fertility. Here, we summarize the roles of RLKs during plant reproduction at the genetic and molecular levels, including RLK-mediated floral organ development, ovule and anther development, and embryogenesis. In addition, the possible molecular regulatory patterns of those RLKs with unrevealed mechanisms during reproductive development are discussed. We also point out the thought-provoking questions raised by the research on these plant RLKs during reproduction for future investigation.
Topics: Arabidopsis; Ovule; Plants; Protein Kinases; Reproduction
PubMed: 35059634
DOI: 10.1016/j.xplc.2021.100273 -
Molecular Biology of the Cell Aug 2021With No Lysine (K) WNK kinases regulate electro-neutral cotransporters that are controlled by osmotic stress and chloride. We showed previously that autophosphorylation...
With No Lysine (K) WNK kinases regulate electro-neutral cotransporters that are controlled by osmotic stress and chloride. We showed previously that autophosphorylation of WNK1 is inhibited by chloride, raising the possibility that WNKs are activated by osmotic stress. Here we demonstrate that unphosphorylated WNK isoforms 3 and 1 autophosphorylate in response to osmotic pressure in vitro, applied with the crowding agent polyethylene glycol (PEG)400 or osmolyte ethylene glycol (EG), and that this activation is opposed by chloride. Small angle x-ray scattering of WNK3 in the presence and absence of PEG400, static light scattering in EG, and crystallography of WNK1 were used to understand the mechanism. Osmosensing in WNK3 and WNK1 appears to occur through a conformational equilibrium between an inactive, unphosphorylated, chloride-binding dimer and an autophosphorylation-competent monomer. An improved structure of the inactive kinase domain of WNK1, and a comparison with the structure of a monophosphorylated form of WNK1, suggests that large cavities, greater hydration, and specific bound water may participate in the osmosensing mechanism. Our prior work showed that osmolytes have effects on the structure of phosphorylated WNK1, suggestive of multiple stages of osmotic regulation in WNKs.
Topics: Autoradiography; Chromatography, Gel; Ethylene Glycol; Osmotic Pressure; Phosphorylation; Polyethylene Glycols; Protein Conformation; Protein Kinases; Protein Multimerization; Scattering, Small Angle; WNK Lysine-Deficient Protein Kinase 1; Water; X-Ray Diffraction
PubMed: 33689398
DOI: 10.1091/mbc.E20-01-0089 -
Journal of Medicinal Chemistry Jan 2023The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its... (Review)
Review
The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its role, as its name suggests, is mainly to regulate cell death. The DAPK family comprises five members, including DAPK1, DAPK2, DAPK3, DRAK1 and DRAK2, which show high homology in the common N-terminal kinase domain but differ in the extra-catalytic domain. Notably, previous research has suggested that the DAPK family plays an essential role in both the development and regulation of human diseases. However, only a few small-molecule inhibitors have been reported. In this Perspective, we mainly discuss the structure, biological function, and role of DAPKs in diseases and the currently discovered small-molecule inhibitors, providing valuable information for the development of the DAPK field.
Topics: Humans; Death-Associated Protein Kinases; Protein Serine-Threonine Kinases; Catalytic Domain; Calcium-Calmodulin-Dependent Protein Kinases
PubMed: 36645394
DOI: 10.1021/acs.jmedchem.2c01606 -
Pharmacological Reviews Oct 2022The number of cancer drugs is increasing as new chemical entities are developed to target molecules, often protein kinases, driving cancer progression. In 2009, Fedorov... (Review)
Review
The number of cancer drugs is increasing as new chemical entities are developed to target molecules, often protein kinases, driving cancer progression. In 2009, Fedorov et al. identified that of the protein kinases in the human kinome, most of the focus has been on a small subset. They highlighted that many poorly investigated protein kinases were cancer drivers, but there was no relationship between publications and involvement in cancer development or progression. Since 2009, there has been a doubling in the number of publications, patents, and drugs targeting the kinome. To determine whether this was an expansion in knowledge of well-studied targets-searching in the light under the lamppost-or an explosion of investigations into previously poorly investigated targets, we searched the literature for publications on each kinase, updating Federov et al.'s assessment of the druggable kinome. The proportion of papers focusing on the 50 most-studied kinases had not changed, and the makeup of those 50 had barely changed. The majority of new drugs (80%) were against the same group of 50 kinases identified as targets 10 years ago, and the proportion of studies investigating previously poorly investigated kinases (1%) was unchanged. With three exceptions [p38 mitogenactivated protein kinase (p38a), AMP-activated protein kinase catalytic -subunit 1,2, and B-Raf proto-oncogene (BRAF) serine/threonine kinase], 95% of publications addressing kinases still focused on a relatively small proportion (50%) of the human kinome independently of their involvement as cancer drivers. There is, therefore, still extensive scope for discovery of therapeutics targeting different protein kinases in cancer and still a bias toward well-characterized targets over the innovative searchlight into the unknown. SIGNIFICANCE STATEMENT: This study presents evidence that drug discovery efforts in cancer are still to some extent focused on a narrow group of well-studied kinases 10 years after the identification of multiple novel cancer targets in the human kinome. This suggests that there is still room for researchers in academia, industry, and the not-for-profit sector to develop new and diverse therapies targeting kinases for cancer.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins B-raf; Serine
PubMed: 36180110
DOI: 10.1124/pharmrev.121.000410 -
Current Opinion in Chemical Biology Aug 2017Reversible protein phosphorylation regulates virtually all aspects of life in the cell. As a result, dysregulation of protein kinases, the enzymes responsible for... (Review)
Review
Reversible protein phosphorylation regulates virtually all aspects of life in the cell. As a result, dysregulation of protein kinases, the enzymes responsible for transferring phosphate groups from ATP to proteins, are often the cause or consequence of many human diseases including cancer. Almost three dozen protein kinase inhibitors (PKIs) have been approved for clinical applications since 1995, the vast majority of them for the treatment of cancer. According to the NCI, there are more than 100 types of cancer. However, FDA-approved PKIs only target 14 of them. Importantly, of the more than 500 protein kinases encoded by the human genome, only 22 are targets for currently approved PKIs, suggesting that the reservoir of PKIs still has room to grow significantly. In this short review we will discuss the most recent advances, challenges, and alternatives to currently adopted strategies in this burgeoning field.
Topics: Adenosine Triphosphate; Drug Discovery; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Kinases; Small Molecule Libraries
PubMed: 28732278
DOI: 10.1016/j.cbpa.2017.06.015