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Article: A small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activity

TitleA small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activity
Authors
Issue Date2002
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 15, p. 10066-10071 How to Cite?
AbstractThe results of previous preclinical and clinical studies have identified angiogenin (ANG) as a potentially important target for anti-cancer therapy. Here we report the design and implementation of a high-throughput screening assay to identify small molecules that bind to the ribonucleolytic active site of ANG, which is critically involved in the induction of angiogenesis by this protein. Screening of 18,310 compounds from the National Cancer Institute (NCI) Diversity Set and ChemBridge DIVERSet yielded 15 hits that inhibit the enzymatic activity of ANG with Ki values < 100 μM. One of these, NCI compound 65828 [8-amino-5-(4′-hydroxybiphenyl-4-ylazo)naphthalene-2-sulfonate; Ki = 81 μM), was selected for more detailed studies. Minor changes in ANG or ligand structure markedly reduced potency, demonstrating that inhibition reflects active-site rather than nonspecific binding; these observations are consistent with a computationally generated model of the ANG·65828 complex. Local treatment with modest doses of 65828 significantly delayed the formation of s.c. tumors from two distinct human cancer cell types in athymic mice. ANG is the likely target involved because (i) a 65828 analogue with much lower potency against the enzymatic activity of ANG failed to exert any antitumor effect, (ii) tumors from 65828-treated mice had fewer interior blood vessels than those from control mice, and (iii) 65828 appears to have no direct effect on the tumor cells. Our findings provide considerable support for the targeting of the enzymatic active site of ANG as a strategy for developing new anticancer drugs.
Persistent Identifierhttp://hdl.handle.net/10722/157348
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKao, RYTen_US
dc.contributor.authorJenkins, JLen_US
dc.contributor.authorOlson, KAen_US
dc.contributor.authorKey, MEen_US
dc.contributor.authorFett, JWen_US
dc.contributor.authorShapiro, Ren_US
dc.date.accessioned2012-08-08T08:49:07Z-
dc.date.available2012-08-08T08:49:07Z-
dc.date.issued2002en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 15, p. 10066-10071en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/157348-
dc.description.abstractThe results of previous preclinical and clinical studies have identified angiogenin (ANG) as a potentially important target for anti-cancer therapy. Here we report the design and implementation of a high-throughput screening assay to identify small molecules that bind to the ribonucleolytic active site of ANG, which is critically involved in the induction of angiogenesis by this protein. Screening of 18,310 compounds from the National Cancer Institute (NCI) Diversity Set and ChemBridge DIVERSet yielded 15 hits that inhibit the enzymatic activity of ANG with Ki values < 100 μM. One of these, NCI compound 65828 [8-amino-5-(4′-hydroxybiphenyl-4-ylazo)naphthalene-2-sulfonate; Ki = 81 μM), was selected for more detailed studies. Minor changes in ANG or ligand structure markedly reduced potency, demonstrating that inhibition reflects active-site rather than nonspecific binding; these observations are consistent with a computationally generated model of the ANG·65828 complex. Local treatment with modest doses of 65828 significantly delayed the formation of s.c. tumors from two distinct human cancer cell types in athymic mice. ANG is the likely target involved because (i) a 65828 analogue with much lower potency against the enzymatic activity of ANG failed to exert any antitumor effect, (ii) tumors from 65828-treated mice had fewer interior blood vessels than those from control mice, and (iii) 65828 appears to have no direct effect on the tumor cells. Our findings provide considerable support for the targeting of the enzymatic active site of ANG as a strategy for developing new anticancer drugs.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshAmino Acid Substitutionen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAnticarcinogenic Agents - Pharmacologyen_US
dc.subject.meshCell Lineen_US
dc.subject.meshDrug Evaluation, Preclinical - Methodsen_US
dc.subject.meshGenetic Variationen_US
dc.subject.meshHumansen_US
dc.subject.meshKineticsen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Nudeen_US
dc.subject.meshMolecular Structureen_US
dc.subject.meshNaphthalenesulfonates - Pharmacologyen_US
dc.subject.meshNeoplasms - Blood - Prevention & Controlen_US
dc.subject.meshNeovascularization, Pathologic - Prevention & Controlen_US
dc.subject.meshRecombinant Proteins - Pharmacologyen_US
dc.subject.meshReproducibility Of Resultsen_US
dc.subject.meshRibonuclease, Pancreatic - Antagonists & Inhibitorsen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.subject.meshTransplantation, Heterologousen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.titleA small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activityen_US
dc.typeArticleen_US
dc.identifier.emailKao, RYT:rytkao@hkucc.hku.hken_US
dc.identifier.authorityKao, RYT=rp00481en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1073/pnas.152342999en_US
dc.identifier.pmid12118120-
dc.identifier.scopuseid_2-s2.0-0037162499en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037162499&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume99en_US
dc.identifier.issue15en_US
dc.identifier.spage10066en_US
dc.identifier.epage10071en_US
dc.identifier.isiWOS:000177042400084-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridKao, RYT=7101675499en_US
dc.identifier.scopusauthoridJenkins, JL=7402867712en_US
dc.identifier.scopusauthoridOlson, KA=7202013963en_US
dc.identifier.scopusauthoridKey, ME=7102357716en_US
dc.identifier.scopusauthoridFett, JW=7005065077en_US
dc.identifier.scopusauthoridShapiro, R=7403082810en_US

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