Kinase-targeted cancer therapies: progress, challenges and future directions

Molecular Cancer, Journal Year: 2018, Volume and Issue: 17(1)

Published: Feb. 15, 2018

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these are associated with cancer initiation and progression. recent development small-molecule kinase inhibitors for the treatment diverse types has proven successful in clinical therapy. Significantly, second most targeted drug targets, after G-protein-coupled receptors. Since first inhibitor, early 1980s, 37 have received FDA approval malignancies such as breast lung cancer. Furthermore, about 150 kinase-targeted drugs phase trials, many kinase-specific preclinical stage development. Nevertheless, factors confound efficacy molecules. Specific tumor genetics, microenvironment, resistance, pharmacogenomics determine how useful compound will be given This review provides an overview discovery relation oncology highlights challenges future potential therapies.

Language: Английский

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Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib

The Lancet, Journal Year: 2007, Volume and Issue: 370(9604), P. 2011 - 2019

Published: Dec. 1, 2007

Language: Английский

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Rational design of inhibitors that bind to inactive kinase conformations

Nature Chemical Biology, Journal Year: 2006, Volume and Issue: 2(7), P. 358 - 364

Published: June 16, 2006

Language: Английский

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Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

Nature Biotechnology, Journal Year: 2007, Volume and Issue: 25(9), P. 1035 - 1044

Published: Aug. 26, 2007

Language: Английский

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Target identification and mechanism of action in chemical biology and drug discovery

Nature Chemical Biology, Journal Year: 2013, Volume and Issue: 9(4), P. 232 - 240

Published: March 18, 2013

Language: Английский

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Advances in immunotherapy for hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(8), P. 525 - 543

Published: April 13, 2021

Hepatocellular carcinoma (HCC) is a prevalent disease with progression that modulated by the immune system. Systemic therapy used in advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy checkpoint has shown strong anti-tumour activity subset patients combination anti-PDL1 antibody atezolizumab VEGF-neutralizing bevacizumab or will soon become standard care as first-line for HCC, whereas anti-PD1 agents nivolumab pembrolizumab are after TKIs several regions. Other strategies such adoptive T-cell transfer, vaccination virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges HCC immunotherapy discovery validation predictive biomarkers, advancing treatment to earlier stages disease, applying liver dysfunction more effective combinatorial sequential approaches. Combinations other systemic local treatments perceived most promising opportunities some already under evaluation large-scale trials. This Review provides up-to-date information on best use currently available immunotherapies therapeutic development. Immunotherapeutic interventions might be tools hepatocellular carcinoma. carcinoma, mechanisms response resistance,

Language: Английский

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Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies

Science, Journal Year: 2007, Volume and Issue: 318(5848), P. 287 - 290

Published: Sept. 14, 2007

Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in brain tumor glioblastoma multiforme (GBM) other solid tumors has been modest. We hypothesized multiple RTKs are coactivated these redundant inputs drive maintain signaling, thereby limiting of targeting single RTKs. Tumor cell lines, xenotransplants, primary indeed show concomitantly activated Combinations RTK inhibitors and/or RNA interference, not agents, decreased survival, anchorage-independent growth even glioma cells deficient PTEN, a frequently inactivated inhibitor PI3K. Thus, effective GBM therapy may require combined regimens

Language: Английский

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Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

Nature Biotechnology, Journal Year: 2011, Volume and Issue: 29(11), P. 1039 - 1045

Published: Oct. 30, 2011

Language: Английский

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Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Nature reviews. Cancer, Journal Year: 2007, Volume and Issue: 7(5), P. 332 - 344

Published: April 24, 2007

Language: Английский

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The target landscape of clinical kinase drugs

Science, Journal Year: 2017, Volume and Issue: 358(6367)

Published: Nov. 30, 2017

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the spectrum 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration phosphoproteomic refined drug-affected pathways, identified response markers, strengthened rationale combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible 2) that modulate cytokine production in primary cells, identifying drugs against lung survival marker MELK (maternal embryonic leucine zipper kinase), repurposing cabozantinib treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via ProteomicsDB database, should facilitate basic, clinical, discovery research aid clinical decision-making.

Language: Английский

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