Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma
Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a...
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Veröffentlicht in: | Cancers 2024-09, Vol.16 (18), p.3177 |
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description | Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable. |
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This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers16183177</identifier><identifier>PMID: 39335149</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Androgens ; Anoikis ; Apoptosis ; Biology ; Bone cancer ; Bone growth ; Cell death ; Cells ; Colon cancer ; Crystal structure ; Drug development ; Drug discovery ; Estrogens ; Ethylenediaminetetraacetic acid ; Hypotheses ; Information sources ; Lung cancer ; Medical innovations ; Melanoma ; Prostate cancer ; Protein folding ; Protein interaction ; Protein structure ; Proteins ; Rankings ; Stem cells ; Structure-function relationships ; Supercomputers ; Toxicity</subject><ispartof>Cancers, 2024-09, Vol.16 (18), p.3177</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2024 by the authors. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c373t-5d0a8706d3ff474dd6ce0cdac80d26bd66fd39a529bff17eb96aa68772e1796e3</cites><orcidid>0000-0003-4856-3569 ; 0000-0001-8690-4876 ; 0000-0002-2342-8347 ; 0000-0003-4180-5051 ; 0000-0001-5067-0203 ; 0000-0003-4181-8127</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11429909/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11429909/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39335149$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Qiao, Fangfang</creatorcontrib><creatorcontrib>Binkowski, Thomas Andrew</creatorcontrib><creatorcontrib>Broughan, Irene</creatorcontrib><creatorcontrib>Chen, Weining</creatorcontrib><creatorcontrib>Natarajan, Amarnath</creatorcontrib><creatorcontrib>Schiltz, Gary E</creatorcontrib><creatorcontrib>Scheidt, Karl A</creatorcontrib><creatorcontrib>Anderson, Wayne F</creatorcontrib><creatorcontrib>Bergan, Raymond</creatorcontrib><title>Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable.</description><subject>Androgens</subject><subject>Anoikis</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Bone cancer</subject><subject>Bone growth</subject><subject>Cell death</subject><subject>Cells</subject><subject>Colon cancer</subject><subject>Crystal structure</subject><subject>Drug development</subject><subject>Drug discovery</subject><subject>Estrogens</subject><subject>Ethylenediaminetetraacetic acid</subject><subject>Hypotheses</subject><subject>Information sources</subject><subject>Lung cancer</subject><subject>Medical innovations</subject><subject>Melanoma</subject><subject>Prostate cancer</subject><subject>Protein folding</subject><subject>Protein interaction</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Rankings</subject><subject>Stem cells</subject><subject>Structure-function relationships</subject><subject>Supercomputers</subject><subject>Toxicity</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkstPGzEQxq0KVBBw5latxIVLwI-NH6cqoi1B4lGpcLYce0xNd-1g7yLx39chlALCPng085tv9NlGaJ_gI8YUPrYmWsiFcCIZEeIT2qZY0Annqt14FW-hvVLucF2sYlx8RltMMTYlrdpG1z9zGiDE5teQRzuMGZqzWJYhg2u-hWLTA-THJvnGNJc17mrVjXXqKjWLKfwJpand87E3sbmAzsTUm1206U1XYO_53EE3P75fn8wn51enZyez84llgg2TqcNGCswd874VrXPcArbOWIkd5QvHuXdMmSlVC--JgIXixnApBAUiFAe2g76udZfjogdnIQ7ZdHqZQ2_yo04m6LeVGH7r2_SgCWmpUlhVhcNnhZzuRyiD7qtp6KoPSGPRjBCssKRCVvTgHXqXxhyrvyeKSUkV_k_dmg50iD7VwXYlqmeSYNlSinmljj6g6nbQB5si-FDzbxqO1w02p1Iy-BeTBOvVZ9DvPkPt-PL6bl74f0_P_gJrL7An</recordid><startdate>20240917</startdate><enddate>20240917</enddate><creator>Qiao, Fangfang</creator><creator>Binkowski, Thomas Andrew</creator><creator>Broughan, Irene</creator><creator>Chen, Weining</creator><creator>Natarajan, Amarnath</creator><creator>Schiltz, Gary E</creator><creator>Scheidt, Karl A</creator><creator>Anderson, Wayne F</creator><creator>Bergan, Raymond</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4856-3569</orcidid><orcidid>https://orcid.org/0000-0001-8690-4876</orcidid><orcidid>https://orcid.org/0000-0002-2342-8347</orcidid><orcidid>https://orcid.org/0000-0003-4180-5051</orcidid><orcidid>https://orcid.org/0000-0001-5067-0203</orcidid><orcidid>https://orcid.org/0000-0003-4181-8127</orcidid></search><sort><creationdate>20240917</creationdate><title>Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma</title><author>Qiao, Fangfang ; 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This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>39335149</pmid><doi>10.3390/cancers16183177</doi><orcidid>https://orcid.org/0000-0003-4856-3569</orcidid><orcidid>https://orcid.org/0000-0001-8690-4876</orcidid><orcidid>https://orcid.org/0000-0002-2342-8347</orcidid><orcidid>https://orcid.org/0000-0003-4180-5051</orcidid><orcidid>https://orcid.org/0000-0001-5067-0203</orcidid><orcidid>https://orcid.org/0000-0003-4181-8127</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Androgens Anoikis Apoptosis Biology Bone cancer Bone growth Cell death Cells Colon cancer Crystal structure Drug development Drug discovery Estrogens Ethylenediaminetetraacetic acid Hypotheses Information sources Lung cancer Medical innovations Melanoma Prostate cancer Protein folding Protein interaction Protein structure Proteins Rankings Stem cells Structure-function relationships Supercomputers Toxicity |
title | Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma |
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