Combinatorial target-guided ligand assembly: Identification of potent subtype-selective c-Src inhibitors

Maly, Dustin J.; Choong, Ingrid; Ellman, Jonathan A.

doi:10.1073/pnas.97.6.2419

Cited by 204 publications

(150 citation statements)

References 29 publications

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“…This finding is broadly important because, in different contexts, both positive (Maly et al, 2000) and negative (Ghoreschi et al, 2009) relationships between potency and specificity have been posited. We found essentially no correlation, indicating that under our experimental and analytical conditions, potency and specificity must essentially be considered independent quantities for drug-metabolizing P450s.…”

Section: Discussionmentioning

confidence: 99%

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Nath¹,

Zientek²,

Burke³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Drug promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug promiscuity are handicapped by the lack of a good way of quantifying promiscuity. In this article, we present a new entropy-based index of drug promiscuity. We apply this index to two high-throughput data sets describing inhibition of cytochrome P450 isoforms by smallmolecule drugs and drug candidates, and we demonstrate how drug promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and promiscuity of small molecules, using a set of fingerprint-based descriptors.

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Section: Discussionmentioning

confidence: 99%

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Nath¹,

Zientek²,

Burke³

et al. 2010

Drug Metab Dispos

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“…Because the inherited or acquired deregulation of protein kinase activity has been implicated in the pathogenesis of many human diseases, including cancer, the inhibition of these enzymes has been postulated as a promising strategy for anticancer treatment, among them is the non-receptor tyrosine kinase c-Src (36,41,42).…”

Section: Discussionmentioning

confidence: 99%

Role of c-Src in Human MCF7 Breast Cancer Cell Tumorigenesis

González

Agulló-Ortuño

García-Martínez

et al. 2006

Journal of Biological Chemistry

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To study the role of c-Src in breast cancer tumorigenesis, we generated a cell line derived from MCF7 carrying an inducible dominant negative c-Src (c-SrcDN: K295M/Y527F) under tetracycline control (Tet-On system). c-SrcDN expression caused phenotypic changes, relocation of c-Src, Fak, and paxillin, and loss of correct actin fiber assembly. These alterations were coupled to increased Fak-Tyr 397 autophosphorylation and to inhibition of Fak-Tyr 925 , p130 CAS , and paxillin phosphorylation. An increased association of total Src with Fak and a decreased interaction of p130 CAS and p85-PI3K with Fak were also observed. SrcDN inhibited cell attachment, spreading, and migration. Serum and EGF-induced stimulation of cell proliferation and Akt phosphorylation were also significantly reduced by SrcDN, whereas p27Kip1 expression was increased. Consistently, silencing c-Src expression by siRNA in MCF7 cells significantly reduced cell migration, attachment, spreading and proliferation. Inoculation of MCF7 cells carrying inducible SrcDN to nude mice generated tumors. However, doxycycline administration to mice significantly reduced tumorigenesis, and when doxycycline treatment was installed after tumor development, a significant tumor regression was observed. In both situations, inhibition of tumorigenesis was associated with decreased Ki67 staining and increased apoptosis in tumors. These data undoubtedly demonstrate the relevance of the Src/Fak complex in breast cancer tumorigenesis.

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“…Herein we report our early results of the design and simplification of azide-bearing N o -methylcarbamoyl-L-arginine substrate as a smaller analog of macrocyclic peptide natural product 1 and the use of target-guided synthesis (TGS) (for reports of TGS, see Rideout, 14 Rideout, 15 Ingelese and Benkovic, 16 Boger et al, 17 Maly et al, 18 Nicolaou et al, 19 Greasley et al, 20 Nguyen and Huc, 21 Nicolaou et al, 22 Kehoe et al, 23 Poulin-Kerstein and Dervan, 24 and Hu et al 25 ) for the screening of new and more potent chitinase inhibitors, using the 1,3-dipolar cycloaddition 26 between an azide ligand and a library of acetylenes. The in situ click chemistry for drug discovery is dependent on irreversibly reacting reagents that are inert under physiological conditions, 27 as shown earlier by the discovery of highly potent inhibitors of acetylcholine esterase, [28][29][30][31] carbonic anhydrase II 32 and HIV-1 protease.…”

Section: Introductionmentioning

confidence: 99%

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

et al. 2009

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In situ click chemistry is a target-guided synthesis technique for discovering potent protein ligands by assembling azides and alkynes into triazoles inside the affinity site of a target protein. We report the rapid discovery of a new and potent inhibitor of bacterial chitinases by the use of in situ click chemistry. We observed a target-templated formation of a potent triazole inhibitor of the chitinase-catalyzed chitin hydrolysis, through in situ click chemistry between a biologically active azide-containing scaffold and structurally unrelated alkyne fragments. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and antiasthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. As a result of our efforts at developing a chitinase inhibitor from an azide-bearing argifin fragment and the application of the chitinase template and a library of alkynes, we rapidly obtained a very potent and new 1,5-disubstituted triazole inhibitor against Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed 300-fold increase in the inhibitory activity against SmChiB compared with that of argifin. To the best of our knowledge, our finding of an enzyme-made 1,5-disubstituted triazole, using in situ click chemistry is the second example reported in the literature.

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Combinatorial target-guided ligand assembly: Identification of potent subtype-selective c-Src inhibitors

Cited by 204 publications

References 29 publications

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Role of c-Src in Human MCF7 Breast Cancer Cell Tumorigenesis

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

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