Natural products as kinase inhibitors

Liu, Jing; Hu, Yi; Waller, David; Wang, Junfeng; Liu, Qingsong

doi:10.1039/c2np00097k

Cited by 51 publications

(29 citation statements)

References 131 publications

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“…(Liu et al, 2012a) One of the most well characterized classes of covalent kinase inhibitors are the resorcylic acid lactones (RALs) with hypothemycin being the most well-known member. (Sonoda et al, 1999) Hypothemycin was originally isolated based on its anti-fungal activity and subsequent investigations demonstrated it to be a covalent protein kinase inhibitor.…”

Section: Overview Of the Currently Developed Irreversible Pkismentioning

confidence: 99%

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Developing Irreversible Inhibitors of the Protein Kinase Cysteinome

Liu

Sabnis

Zhao

et al. 2013

Chemistry & Biology

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Protein kinases are a large family of approximately 530 highly conserved enzymes that transfer a γ-phosphate group from ATP to a variety of amino acid residues such as tyrosine, serine and threonine which serves as a ubiquitous mechanism for cellular signal transduction. The clinical success of a number of kinase-directed drugs and the frequent observation of disease causing mutations in protein kinases suggest that a large number of kinases may represent therapeutically relevant targets. To-date the majority of clinical and preclinical kinase inhibitors are ATP-competitive, non-covalent inhibitors that achieve selectivity through recognition of unique features of particular protein kinases. Recently there has been renewed interest in the development of irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket. Irreversible kinase inhibitors have a number of potential advantages including prolonged pharmacodynamics, suitability for rational design, high potency and ability to validate pharmacological specificity through mutation of the reactive cysteine residue. Here we review recent efforts to develop cysteine-targeted irreversible protein kinase inhibitors and discuss their modes of recognizing the ATP-binding pocket and their biological activity profiles. In addition, we provided an informatics assessment of the potential ‘kinase-cysteinome’ and discuss strategies for the efficient development of new covalent inhibitors.

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Section: Overview Of the Currently Developed Irreversible Pkismentioning

confidence: 99%

“…Irreversible binding has been indicated using mutagenesis or biochemical experiments (Liu et al, 2012a), however crystallographic information is not yet available.…”

Section: Overview Of the Currently Developed Irreversible Pkismentioning

confidence: 99%

Developing Irreversible Inhibitors of the Protein Kinase Cysteinome

Liu

Sabnis

Zhao

et al. 2013

Chemistry & Biology

Self Cite

604

600

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“…Due to their unique structures and important biological bioactivities, this family of compounds has attracted much attention ever since its discovery. ICZs have been found to inhibit protein kinase, topoisomerase and ATP-binding cassette transporter [2,5,6,7,8,9]. Several ICZs, such as UCN-01 (7-hydroxy-STA), lestaurtinib (CEP-701), midostaurin (PKC412), edotecarin, becatecarin and NSC655649, are presently undergoing clinical trials for novel antitumor therapies [10].…”

Section: Introductionmentioning

confidence: 99%

Cloning, Characterization and Heterologous Expression of the Indolocarbazole Biosynthetic Gene Cluster from Marine-Derived Streptomyces sanyensis FMA

Cui

et al. 2013

Marine Drugs

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The indolocarbazole (ICZ) alkaloids have attracted much attention due to their unique structures and potential therapeutic applications. A series of ICZs were recently isolated and identified from a marine-derived actinomycete strain, Streptomyces sanyensis FMA. To elucidate the biosynthetic machinery associated with ICZs production in S. sanyensis FMA, PCR using degenerate primers was carried out to clone the FAD-dependent monooxygenase gene fragment for ICZ ring formation, which was used as a probe to isolate the 34.6-kb DNA region containing the spc gene cluster. Sequence analysis revealed genes for ICZ ring formation (spcO, D, P, C), sugar unit formation (spcA, B, E, K, J, I), glycosylation (spcN, G), methylation (spcMA, MB), as well as regulation (spcR). Their involvement in ICZ biosynthesis was confirmed by gene inactivation and heterologous expression in Streptomyces coelicolor M1152. This work represents the first cloning and characterization of an ICZ gene cluster isolated from a marine-derived actinomycete strain and would be helpful for thoroughly understanding the biosynthetic mechanism of ICZ glycosides.

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“…Several biologically active NPs, such as vincristine, irinotecan, etoposide, and paclitaxel, have been extensively explored as drug candidates for clinical applications as well as basic research tools to investigate biological processes [1]. With the advent of combinatorial chemistry, there had been a decreased interest in natural products for NPs-based drug discovery in the 1980s and 1990s.…”

Section: Introductionmentioning

confidence: 99%

Web search and data mining of natural products and their bioactivities in PubChem

et al. 2013

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Natural products, as major resources for drug discovery historically, are gaining more attentions recently due to the advancement in genomic sequencing and other technologies, which makes them attractive and amenable to drug candidate screening. Collecting and mining the bioactivity information of natural products are extremely important for accelerating drug development process by reducing cost. Lately, a number of publicly accessible databases have been established to facilitate the access to the chemical biology data for small molecules including natural products. Thus, it is imperative for scientists in related fields to exploit these resources in order to expedite their researches on natural products as drug leads/candidates for disease treatment. PubChem, as a public database, contains large amounts of natural products associated with bioactivity data. In this review, we introduce the information system provided at PubChem, and systematically describe the applications for a set of PubChem web services for rapid data retrieval, analysis, and downloading of natural products. We hope this work can serve as a starting point for the researchers to perform data mining on natural products using PubChem.

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Natural products as kinase inhibitors

Cited by 51 publications

References 131 publications

Developing Irreversible Inhibitors of the Protein Kinase Cysteinome

Developing Irreversible Inhibitors of the Protein Kinase Cysteinome

Cloning, Characterization and Heterologous Expression of the Indolocarbazole Biosynthetic Gene Cluster from Marine-Derived Streptomyces sanyensis FMA

Web search and data mining of natural products and their bioactivities in PubChem

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