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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cancers 2024-09, Vol.16 (18), p.3177
Hauptverfasser: Qiao, Fangfang, Binkowski, Thomas Andrew, Broughan, Irene, Chen, Weining, Natarajan, Amarnath, Schiltz, Gary E, Scheidt, Karl A, Anderson, Wayne F, Bergan, Raymond
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page
container_issue 18
container_start_page 3177
container_title Cancers
container_volume 16
creator Qiao, Fangfang
Binkowski, Thomas Andrew
Broughan, Irene
Chen, Weining
Natarajan, Amarnath
Schiltz, Gary E
Scheidt, Karl A
Anderson, Wayne F
Bergan, Raymond
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.
doi_str_mv 10.3390/cancers16183177
format Article
fullrecord <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11429909</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A810842206</galeid><sourcerecordid>A810842206</sourcerecordid><originalsourceid>FETCH-LOGICAL-c373t-5d0a8706d3ff474dd6ce0cdac80d26bd66fd39a529bff17eb96aa68772e1796e3</originalsourceid><addsrcrecordid>eNptkstPGzEQxq0KVBBw5latxIVLwI-NH6cqoi1B4lGpcLYce0xNd-1g7yLx39chlALCPng085tv9NlGaJ_gI8YUPrYmWsiFcCIZEeIT2qZY0Annqt14FW-hvVLucF2sYlx8RltMMTYlrdpG1z9zGiDE5teQRzuMGZqzWJYhg2u-hWLTA-THJvnGNJc17mrVjXXqKjWLKfwJpand87E3sbmAzsTUm1206U1XYO_53EE3P75fn8wn51enZyez84llgg2TqcNGCswd874VrXPcArbOWIkd5QvHuXdMmSlVC--JgIXixnApBAUiFAe2g76udZfjogdnIQ7ZdHqZQ2_yo04m6LeVGH7r2_SgCWmpUlhVhcNnhZzuRyiD7qtp6KoPSGPRjBCssKRCVvTgHXqXxhyrvyeKSUkV_k_dmg50iD7VwXYlqmeSYNlSinmljj6g6nbQB5si-FDzbxqO1w02p1Iy-BeTBOvVZ9DvPkPt-PL6bl74f0_P_gJrL7An</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3110388290</pqid></control><display><type>article</type><title>Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma</title><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><creator>Qiao, Fangfang ; Binkowski, Thomas Andrew ; Broughan, Irene ; Chen, Weining ; Natarajan, Amarnath ; Schiltz, Gary E ; Scheidt, Karl A ; Anderson, Wayne F ; Bergan, Raymond</creator><creatorcontrib>Qiao, Fangfang ; Binkowski, Thomas Andrew ; Broughan, Irene ; Chen, Weining ; Natarajan, Amarnath ; Schiltz, Gary E ; Scheidt, Karl A ; Anderson, Wayne F ; Bergan, Raymond</creatorcontrib><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><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 ; Binkowski, Thomas Andrew ; Broughan, Irene ; Chen, Weining ; Natarajan, Amarnath ; Schiltz, Gary E ; Scheidt, Karl A ; Anderson, Wayne F ; Bergan, Raymond</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c373t-5d0a8706d3ff474dd6ce0cdac80d26bd66fd39a529bff17eb96aa68772e1796e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Androgens</topic><topic>Anoikis</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Bone cancer</topic><topic>Bone growth</topic><topic>Cell death</topic><topic>Cells</topic><topic>Colon cancer</topic><topic>Crystal structure</topic><topic>Drug development</topic><topic>Drug discovery</topic><topic>Estrogens</topic><topic>Ethylenediaminetetraacetic acid</topic><topic>Hypotheses</topic><topic>Information sources</topic><topic>Lung cancer</topic><topic>Medical innovations</topic><topic>Melanoma</topic><topic>Prostate cancer</topic><topic>Protein folding</topic><topic>Protein interaction</topic><topic>Protein structure</topic><topic>Proteins</topic><topic>Rankings</topic><topic>Stem cells</topic><topic>Structure-function relationships</topic><topic>Supercomputers</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qiao, Fangfang</au><au>Binkowski, Thomas Andrew</au><au>Broughan, Irene</au><au>Chen, Weining</au><au>Natarajan, Amarnath</au><au>Schiltz, Gary E</au><au>Scheidt, Karl A</au><au>Anderson, Wayne F</au><au>Bergan, Raymond</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2024-09-17</date><risdate>2024</risdate><volume>16</volume><issue>18</issue><spage>3177</spage><pages>3177-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>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.</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>
fulltext fulltext
identifier ISSN: 2072-6694
ispartof Cancers, 2024-09, Vol.16 (18), p.3177
issn 2072-6694
2072-6694
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11429909
source MDPI - Multidisciplinary Digital Publishing Institute; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T02%3A42%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Protein%20Structure%20Inspired%20Discovery%20of%20a%20Novel%20Inducer%20of%20Anoikis%20in%20Human%20Melanoma&rft.jtitle=Cancers&rft.au=Qiao,%20Fangfang&rft.date=2024-09-17&rft.volume=16&rft.issue=18&rft.spage=3177&rft.pages=3177-&rft.issn=2072-6694&rft.eissn=2072-6694&rft_id=info:doi/10.3390/cancers16183177&rft_dat=%3Cgale_pubme%3EA810842206%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3110388290&rft_id=info:pmid/39335149&rft_galeid=A810842206&rfr_iscdi=true