ATP site-directed competitive and irreversible inhibitors of protein kinases

García‐Echeverría, Carlos; Traxler, Peter; Evans, Dean B.

doi:10.1002/(sici)1098-1128(200001)20:1<28::aid-med2>3.0.co;2-2

Cited by 114 publications

(7 citation statements)

References 119 publications

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“…With over 500 members, the kinase family has received a high degree of attention from academic researchers as well as pharmaceutical industries [ 147 ]. After the clearance of possible hindrances, owing to the high degree of active site similarities and possible off-target activity, kinase inhibitors have gained scientific limelight [ 21 , 24 , 78 , 148 , 149 ]. In a 13-year summary of targeted therapies including kinase inhibitors, the clinical success rate of kinase inhibitors was superior to other cancer therapies [ 150 , 151 ].…”

Section: Recent Clinical Developmentsmentioning

confidence: 99%

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

et al. 2018

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

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Section: Recent Clinical Developmentsmentioning

confidence: 99%

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

et al. 2018

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“…However, more than 500 human protein kinases are known and they share high structural conservation in the ATP-binding site. Therefore, achieving a significant degree of target selectivity via the ATP binding site is an imposing problem (Toledo et al , 1999; Garcia-Echeverria et al , 2000). This challenge has been met for several compounds, such as lapatinib, which shows impressive selectivity for EGFR (Karaman et al , 2008).…”

Section: Introductionmentioning

confidence: 99%

In Situ Kinase Profiling Reveals Functionally Relevant Properties of Native Kinases

Patricelli¹,

Nomanbhoy²,

Wu³

et al. 2011

Chemistry & Biology

301

377

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Summary Protein kinases are intensely studied mediators of cellular signaling, yet important questions remain regarding their regulation and in vivo properties. Here we use a probe-based chemoprotemics platform to profile several well studied kinase inhibitors against more than 200 kinases in native cell proteomes and reveal new biological targets for some of these inhibitors. Several striking differences were identified between native and recombinant kinase inhibitory profiles, in particular, for the Raf kinases. The native kinase binding profiles presented here closely mirror the cellular activity of these inhibitors, even when the inhibition profiles differ dramatically from recombinant assay results. Additionally, Raf activation events could be detected upon live cell treatment with inhibitors. These studies highlight the complexities of protein kinase behavior in the cellular context and demonstrate that profiling with only recombinant/purified enzymes can be misleading.

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“…It is known that the active and inactive conformations are significantly different [71,72]. Examples of inhibitors that bind an inactive kinase conformation include Gleevec (Abl) [73,74] BIRB 796 (p38) [75] and AAL993 (VEGF-R) [76].…”

Section: Introductionmentioning

confidence: 99%

The PI3K/Akt Pathway: Recent Progress in the Development of ATP-Competitive and Allosteric Akt Kinase Inhibitors

Lindsley¹,

Barnett²,

Layton³

et al. 2008

CCDT

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This article describes recent advances in the development and biological evaluation of allosteric and ATP-competitive small molecule inhibitors for the serine/threonine kinase Akt (protein kinase B, PKB). Unregulated activation of the PI3K/Akt/PTEN pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers making Akt an exciting new target for cancer therapy. The development of Akt inhibitors has been complicated and hampered by the presence of three Akt isozymes, (Akt1, Akt2 and Akt3) which differ in function and tissue distribution, as well as a lack of Akt specific inhibitors. In the past 18 months, a large number of reports have appeared describing the discovery and development of allosteric Akt kinase inhibitors and classical ATP-competitive Akt kinase inhibitors. This review will discuss the PI3K/Akt/PTEN pathway, allosteric and ATP-competitive Akt kinase inhibitors, their biological evaluation and progress towards target validation.

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ATP site-directed competitive and irreversible inhibitors of protein kinases

Cited by 114 publications

References 119 publications

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

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

In Situ Kinase Profiling Reveals Functionally Relevant Properties of Native Kinases

The PI3K/Akt Pathway: Recent Progress in the Development of ATP-Competitive and Allosteric Akt Kinase Inhibitors

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