Duke University assistant professor Emily Derbyshire and colleagues identified more than 30 enzyme - blocking molecules, called
protein kinase inhibitors, that curb malaria before symptoms start.
A class of therapeutic drugs known as
protein kinase inhibitors has in the past decade become a powerful weapon in the fight against various life - threatening diseases, including certain types of leukemia, lung cancer, kidney cancer and squamous cell cancer of the head and neck.
Focusing on a particular group of enzyme - blocking compounds called
protein kinase inhibitors, they identified 31 compounds that inhibit malaria growth without harming the host.
20) and several chemical drugs including mitogen - activated
protein kinase inhibitor and histone deacetylase inhibitor (21, 22).
Not exact matches
And none of these
kinase inhibitors have yet been rigorously tested in a head - to - head comparison with the
protein therapies already on the market.
One of the more intriguing findings in the study was that increasing histone crotonylation works synergistically with other known anti-HIV latency molecules, such as the
protein kinase C agonist PEP005 and the HDAC
inhibitor vorinostat.
One option is an MEK
inhibitor, which inhibits the mitogen - activated
protein kinase enzymes used to therapeutically affect the MAPK pathway that is often overactive in cancers.
THE STUDIES A trilogy of papers published in the September 28 issue of Nature examine the role of a
protein — cyclin - dependent
kinase inhibitor p16INK4a — in aging, healing, and cancer.
As the name suggests,
kinase inhibitors interrupt the function of
kinases — a particular type of enzyme — and effectively shut down the activity of
proteins that contribute to cancer.
These therapies, the first an antibody and the second of a class called tyrosine
kinase inhibitors (TKIs), reduce the ability of a target gene to manufacture the
protein it encodes.
Rho -
kinase inhibitor Y - 27632 and hypoxia synergistically enhance chondrocytic phenotype and change the S100
protein profile in human chondrosarcoma cells
The enzymes that phosphorylate
proteins are called
kinases, and many new cancer drugs are
kinase inhibitors.
This thesis primarily investigates the effects of mechanical cyclic stretching, a 5 % low oxygen atmosphere and the Rho -
kinase inhibitor, Y - 27632, on
protein responses in chondrocytic human chondrosarcoma (HCS - 2 / 8) cells.
Larotrectinib, a highly selective
inhibitor of all three tropomyosin receptor
kinase (TRK)
proteins, was recently shown to have marked and sustained antitumor activity in patients with TRK fusion — positive cancers, according to an analysis of three phase I and II cohorts.
The cyclin - dependent
kinase (CDK)
inhibitors p21waf1 and p27kip1 and underphosphorylated retinoblastoma
protein levels were up - regulated and cyclin A levels were decreased in a concentration - dependent manner (Fig. 5B and C).
The Raf ‐ 1
kinase inhibitor protein participates in the pathogenesis of IL ‐ 17 ‐ mediated autoimmune diseases and inflammation by promoting the formation of the IL ‐ 17RA ‐ Act1 complex, required for downstream signaling and cytokine production.
The researchers also screened more than 100 anticancer compounds to see whether they killed lab - grown cancer cells from the devils and found that both strains responded to
inhibitors of
proteins known as receptor tyrosine
kinases.
Similarly, inhibiting ABL
kinase activity with the allosteric
inhibitor GNF5 decreased TAZ
protein abundance (fig.
Abbreviations: ASC, apoptosis - associated speck - like
protein containing a caspase - recruitment domain; ATM, adipose - tissue - resident macrophage; BAT, brown adipose tissue; CCR2, CC chemokine receptor 2; CHOP, C / EBP (CCAAT / enhancer - binding
protein)- homologous
protein; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; GPCR, G -
protein - coupled receptor; HIF, hypoxia - inducible factor; IFNγ, interferon γ; IKK,
inhibitor of nuclear factor κB
kinase; IL, interleukin; IRS - 1, insulin receptor substrate - 1; JNK, c - Jun N - terminal
kinase; LDL, low - density lipoprotein; Ldlr, LDL receptor; LXR, liver X receptor; MCP - 1, monocyte chemoattractant
protein 1; miRNA, microRNA; mTOR, mammalian target of rapamycin; NAFLD, non-alcoholic fatty liver disease; NF - κB, nuclear factor κB; NLRP3, NLR (nucleotide - binding - domain - and leucine - rich - repeat - containing) family, pyrin - domain - containing 3; oxLDL, oxidized LDL; PKR, double - stranded RNA - dependent
protein kinase; PPAR, peroxisome - proliferator - activated receptor; STAT6, signal transducer and activator of transcription 6; SVF, stromal vascular fraction; TLR, Toll - like receptor; TNFα, tumour necrosis factor α; UPR, unfolded
protein response; WAT, white adipose tissue
Stephen Alexander, UK - Cannabinoid receptors, transporters, endocannabinoid turnover, hydrogen sulphide turnover Arthur Christopoulos, Australia (GPCRs Liaison)- G
protein - coupled receptors; analytical pharmacology; allosteric modulation; biased agonism; drug discovery; neuropharmacology John Cidlowski, USA (NHRs Liaison)- Glucocorticoid receptor signaling; apoptosis and the immune system Anthony P. Davenport, UK (Chair Evolving Pharmacology, GPCRs Liaison) Doriano Fabbro, Switzerland -
Kinases and their biology,
kinase inhibitors, drug discovery, pharmacology of drugs (
kinase inhibitors) in the indication oncology, biology of oncology Kozo Kaibuchi, Japan Yoshikatsu Kanai, Japan - Transporters, amino acid signals, epithelial function, cancer biology Francesca Levi - Schaffer, Israel - eosinophils and mast cells as effector cells in allergic inflammation: characterization of new receptors / ligands, hypoxia / angiogenesis and eosinophils, asthma, atopic dermatitis, allergic rhinitis, immunopharmacological modulation of allergic diseases by bispecific recombinant antibodies, bacteria interactions with eosinophils and mast cells, the allergic effector unit, mast cell derived tumors: new antibody based treatment, the allergic inflammation and the resolvome, non IgE - mediated mast cell activation in diseases Eliot H. Ohlstein, USA (Editor)- Drug discovery and development, urogenital biology, cardiovascular / metabolic medicine John A. Peters, UK (LGICs Liaison) Alex Phipps, UK - Oncology, Clinical Pharmacology, Biologics and Immunotherapy Joerg Striessnig, Austria (VGICs Liaison)- Physiology, pharmacology and pathophysiological role of voltage-gated calcium channels
Susan Amara, USA - «Regulation of transporter function and trafficking by amphetamines, Structure - function relationships in excitatory amino acid transporters (EAATs), Modulation of dopamine transporters (DAT) by GPCRs, Genetics and functional analyses of human trace amine receptors» Tom I. Bonner, USA (Past Core Member)- Genomics, G
protein coupled receptors Michel Bouvier, Canada - Molecular Pharmacology of G
protein - Coupled Receptors; Molecular mechanisms controlling the selectivity and efficacy of GPCR signalling Thomas Burris, USA - Nuclear Receptor Pharmacology and Drug Discovery William A. Catterall, USA (Past Core Member)- The Molecular Basis of Electrical Excitability Steven Charlton, UK - Molecular Pharmacology and Drug Discovery Moses Chao, USA - Mechanisms of Neurotophin Receptor Signaling Mark Coles, UK - Cellular differentiation, human embryonic stem cells, stromal cells, haematopoietic stem cells, organogenesis, lymphoid microenvironments, develomental immunology Steven L. Colletti, USA Graham L Collingridge, UK Philippe Delerive, France - Metabolic Research (diabetes, obesity, non-alcoholic fatty liver, cardio - vascular diseases, nuclear hormone receptor, GPCRs,
kinases) Sir Colin T. Dollery, UK (Founder and Past Core Member) Richard M. Eglen, UK Stephen M. Foord, UK David Gloriam, Denmark - GPCRs, databases, computational drug design, orphan recetpors Gillian Gray, UK Debbie Hay, New Zealand - G
protein - coupled receptors, peptide receptors, CGRP, Amylin, Adrenomedullin, Migraine, Diabetes / obesity Allyn C. Howlett, USA Franz Hofmann, Germany - Voltage dependent calcium channels and the positive inotropic effect of beta adrenergic stimulation; cardiovascular function of cGMP
protein kinase Yu Huang, Hong Kong - Endothelial and Metabolic Dysfunction, and Novel Biomarkers in Diabetes, Hypertension, Dyslipidemia and Estrogen Deficiency, Endothelium - derived Contracting Factors in the Regulation of Vascular Tone, Adipose Tissue Regulation of Vascular Function in Obesity, Diabetes and Hypertension, Pharmacological Characterization of New Anti-diabetic and Anti-hypertensive Drugs, Hypotensive and antioxidant Actions of Biologically Active Components of Traditional Chinese Herbs and Natural Plants including Polypehnols and Ginsenosides Adriaan P. IJzerman, The Netherlands - G
protein - coupled receptors; allosteric modulation; binding kinetics Michael F Jarvis, USA - Purines and Purinergic Receptors and Voltage-gated ion channel (sodium and calcium) pharmacology Pain mechanisms Research Reproducibility Bong - Kiun Kaang, Korea - G
protein - coupled receptors; Glutamate receptors; Neuropsychiatric disorders Eamonn Kelly, Prof, UK - Molecular Pharmacology of G
protein - coupled receptors, in particular opioid receptors, regulation of GPCRs by kinasis and arrestins Terry Kenakin, USA - Drug receptor pharmacodynamics, receptor theory Janos Kiss, Hungary - Neurodegenerative disorders, Alzheimer's disease Stefan Knapp, Germany - Rational design of highly selective
inhibitors (so call chemical probes) targeting
protein kinases as well as
protein interaction
inhibitors of the bromodomain family Andrew Knight, UK Chris Langmead, Australia - Drug discovery, GPCRs, neuroscience and analytical pharmacology Vincent Laudet, France (Past Core Member)- Evolution of the Nuclear Receptor / Ligand couple Margaret R. MacLean, UK - Serotonin, endothelin, estrogen, microRNAs and pulmonary hyperten Neil Marrion, UK - Calcium - activated potassium channels, neuronal excitability Fiona Marshall, UK - GPCR molecular pharmacology, structure and drug discovery Alistair Mathie, UK - Ion channel structure, function and regulation, pain and the nervous system Ian McGrath, UK - Adrenoceptors; autonomic transmission; vascular pharmacology Graeme Milligan, UK - Structure, function and regulation of G
protein - coupled receptors Richard Neubig, USA (Past Core Member)- G
protein signaling; academic drug discovery Stefan Offermanns, Germany - G
protein - coupled receptors, vascular / metabolic signaling Richard Olsen, USA - Structure and function of GABA - A receptors; mode of action of GABAergic drugs including general anesthetics and ethanol Jean - Philippe Pin, France (Past Core Member)- GPCR - mGLuR - GABAB - structure function relationship - pharmacology - biophysics Helgi Schiöth, Sweden David Searls, USA - Bioinformatics Graeme Semple, USA - GPCR Medicinal Chemistry Patrick M. Sexton, Australia - G
protein - coupled receptors Roland Staal, USA - Microglia and neuroinflammation in neuropathic pain and neurological disorders Bart Staels, France - Nuclear receptor signaling in metabolic and cardiovascular diseases Katerina Tiligada, Greece - Immunopharmacology, histamine, histamine receptors, hypersensitivity, drug allergy, inflammation Georg Terstappen, Germany - Drug discovery for neurodegenerative diseases with a focus on AD Mary Vore, USA - Activity and regulation of expression and function of the ATP - binding cassette (ABC) transporters
Similar results were obtained for the
protein tyrosine
kinase inhibitor regorafenib (data not shown).
Abbreviations: Aβ, amyloid β - peptide; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; Ambra1, activating molecule in Beclin -1-regulated autophagy; AMPK, AMP - activated
protein kinase; APP, amyloid precursor
protein; AR, androgen receptor; Atg, autophagy - related; AV, autophagic vacuole; Bcl, B - cell lymphoma; BH3, Bcl - 2 homology 3; CaMKKβ, Ca2 + - dependent
protein kinase kinase β; CHMP2B, charged multivesicular body
protein 2B; CMA, chaperone - mediated autophagy; 2 ′ 5 ′ ddA, 2 ′, 5 ′ - dideoxyadenosine; deptor, DEP - domain containing mTOR - interacting
protein; DRPLA, dentatorubral pallidoluysian atrophy; 4E - BP1, translation initiation factor 4E - binding
protein - 1; Epac, exchange
protein directly activated by cAMP; ER, endoplasmic reticulum; ERK1 / 2, extracellular - signal - regulated
kinase 1/2; ESCRT, endosomal sorting complex required for transport; FAD, familial AD; FDA, U.S. Food and Drug Administration; FIP200, focal adhesion
kinase family - interacting
protein of 200 kDa; FoxO3, forkhead box O3; FTD, frontotemporal dementia; FTD3, FTD linked to chromosome 3; GAP, GTPase - activating
protein; GR, guanidine retinoid; GSK3, glycogen synthase
kinase 3; HD, Huntington's disease; hiPSC, human induced pluripotent stem cell; hVps, mammalian vacuolar
protein sorting homologue; IKK,
inhibitor of nuclear factor κB
kinase; IMPase, inositol monophosphatase; IP3R, Ins (1,4,5) P3 receptor; I1R, imidazoline - 1 receptor; JNK1, c - Jun N - terminal
kinase 1; LC3, light chain 3; LD, Lafora disease; L - NAME, NG - nitro - L - arginine methyl ester; LRRK2, leucine - rich repeat
kinase 2; MIPS, myo - inositol -1-phosphate synthase; mLST8, mammalian lethal with SEC13
protein 8; MND, motor neuron disease; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; MVB, multivesicular body; NAC, N - acetylcysteine; NBR1, neighbour of BRCA1 gene 1; NOS, nitric oxide synthase; p70S6K, ribosomal
protein S6
kinase - 1; PD, Parkinson's disease; PDK1, phosphoinositide - dependent
kinase 1; PE, phosphatidylethanolamine; PI3K, phosphoinositide 3 -
kinase; PI3KC1a, class Ia PI3K; PI3KC3, class III PI3K; PI3KK, PI3K - related
protein kinase; PINK1, PTEN - induced
kinase 1; PKA,
protein kinase A; PLC, phospholipase C; polyQ, polyglutamine; PS, presenilin; PTEN, phosphatase and tensin homologue deleted from chromosome 10; Rag, Ras - related GTP - binding
protein; raptor, regulatory - associated
protein of mTOR; Rheb, Ras homologue enriched in brain; rictor, rapamycin - insensitive companion of mTOR; SBMA, spinobulbar muscular atrophy; SCA, spinocerebellar ataxia; SLC, solute carrier; SMER, small - molecule enhancer of rapamycin; SMIR, small - molecule
inhibitor of rapamycin; SNARE, N - ethylmaleimide - sensitive factor - attachment
protein receptor; SOD1, copper / zinc superoxide dismutase 1; TFEB, transcription factor EB; TOR, target of rapamycin; TSC, tuberous sclerosis complex; ULK1, UNC -51-like
kinase 1; UVRAG, UV irradiation resistance - associated gene; VAMP, vesicle - associated membrane
protein; v - ATPase, vacuolar H + - ATPase; Vps, vacuolar
protein sorting
Specifically, my research proposal addresses the mechanisms by which the
kinase 3 - phosphoinoside dependent
protein kinase - 1 (PDK1) mediates resistance to cell cycle related CDK4 / 6 inhibition in ER + breast cancer and explores the in vivo effects of inhibiting PDK1 in combination with CDK4 / 6
inhibitors toward ER + breast cancer growth.
Concordantly, inhibition of the cGMP - dependent
protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP - phosphodiesterase
inhibitor circumvents egress repression by PKAc1 or pH neutralisation.
Dr. Kutzkey was formerly a scientist at KAI Pharmaceuticals, focused on the discovery and development of selective
protein kinase C
inhibitors.
Chemotype Evolution has identified nanomolar
inhibitors of
kinases and
protein -
protein interactions starting from molecules with micromolar to millimolar potency.
Genistein Inhibits Both Estrogen and Growth Factor — stimulated Proliferation of Human Breast Cancer Cells Cell Growth & Differentiation 1996 (Oct); 7 (10): 1345 — 1351 Genistein is a naturally occurring dietary
protein tyrosine
kinase (PTK)
inhibitor that is hypothesized to be responsible for the lower rate of breast cancer observed in Asian women consuming soy.
• S. Dey, Development of Enzyme - Based Screening Methodology for Combinatorial catalysis — Identification of Novel Chiral Salens for the Hydrolytic Kinetic Resolution of Epoxides, Dissertation, 2007, University of Nebraska • B. J. Morgan, S. Dey, S. W. Johnson, and M. C. Kozlowski, Design, Synthesis and Investigation of
Protein Kinase C
Inhibitors: Total Syntheses of (+)- Calphostin D, (+)- Phleichrome, Cercosporin and Novel Perylenequinones, J. Am.