Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors
Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's...
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| creator | Anchoori, Ravi K George, Logan Tseng, Ssu-Hsueh Lam, Brandon Polkampally, Srinidhi Amiano, Anjali D Foran, Palmer Tsingine, Hannah Samanapally, Harideep Carrizo Velasquez, Fernanda Das, Samarjit Xing, Deyin Bin Salam, Ahmad Karanam, Balasubramanyam Hung, Chien-Fu Roden, Richard B S |
| description | Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer. |
| doi_str_mv | 10.1371/journal.pone.0256937 |
| format | Article |
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Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0256937</identifier><identifier>PMID: 34506530</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analogs ; Analysis ; Anesthesiology ; Animals ; Annexin V ; Antibodies ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Asymmetry ; Benzylidene Compounds - chemistry ; Benzylidene Compounds - pharmacology ; Binding ; Biology and Life Sciences ; Bioluminescence ; Biomarkers ; Bortezomib ; BRCA2 protein ; Breast cancer ; Cancer ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemical bonds ; Chirality ; Cisplatin ; Clustering ; Critical care ; Cytotoxicity ; Deoxyribonucleic acid ; Depletion ; Depolarization ; DNA ; DNA damage ; DNA repair ; Doxorubicin ; Drug delivery ; Drug dosages ; Female ; Gene expression ; Glutathione ; Glycolysis ; Gynecological cancer ; Health aspects ; Humans ; Inhibitors ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Lysates ; Medical research ; Medicine and Health Sciences ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Mitochondria ; Molecular weight ; Multiple myeloma ; NMR ; Nuclear magnetic resonance ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - drug therapy ; Oxidative stress ; Pathology ; Peptides ; Physical Sciences ; Proteasome inhibitors ; Proteins ; Research and Analysis Methods ; Solid tumors ; Toxicity ; Tumor cell lines ; Tumors ; Ubiquitin ; Ubiquitination ; Ubiquitination - drug effects</subject><ispartof>PloS one, 2021-09, Vol.16 (9), p.e0256937-e0256937</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Anchoori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Anchoori et al 2021 Anchoori et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-95674e5c191bd9ebd8ab3a9b603c5ddd5d8d3ca061f4d412f47c6ae12724e9a93</citedby><cites>FETCH-LOGICAL-c692t-95674e5c191bd9ebd8ab3a9b603c5ddd5d8d3ca061f4d412f47c6ae12724e9a93</cites><orcidid>0000-0003-1800-8644 ; 0000-0002-2506-0195</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/PMC8432795/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432795/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34506530$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bera, Soumen</contributor><creatorcontrib>Anchoori, Ravi K</creatorcontrib><creatorcontrib>George, Logan</creatorcontrib><creatorcontrib>Tseng, Ssu-Hsueh</creatorcontrib><creatorcontrib>Lam, Brandon</creatorcontrib><creatorcontrib>Polkampally, Srinidhi</creatorcontrib><creatorcontrib>Amiano, Anjali D</creatorcontrib><creatorcontrib>Foran, Palmer</creatorcontrib><creatorcontrib>Tsingine, Hannah</creatorcontrib><creatorcontrib>Samanapally, Harideep</creatorcontrib><creatorcontrib>Carrizo Velasquez, Fernanda</creatorcontrib><creatorcontrib>Das, Samarjit</creatorcontrib><creatorcontrib>Xing, Deyin</creatorcontrib><creatorcontrib>Bin Salam, Ahmad</creatorcontrib><creatorcontrib>Karanam, Balasubramanyam</creatorcontrib><creatorcontrib>Hung, Chien-Fu</creatorcontrib><creatorcontrib>Roden, Richard B S</creatorcontrib><title>Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.</description><subject>Analogs</subject><subject>Analysis</subject><subject>Anesthesiology</subject><subject>Animals</subject><subject>Annexin V</subject><subject>Antibodies</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Asymmetry</subject><subject>Benzylidene Compounds - chemistry</subject><subject>Benzylidene Compounds - pharmacology</subject><subject>Binding</subject><subject>Biology and Life Sciences</subject><subject>Bioluminescence</subject><subject>Biomarkers</subject><subject>Bortezomib</subject><subject>BRCA2 protein</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemical bonds</subject><subject>Chirality</subject><subject>Cisplatin</subject><subject>Clustering</subject><subject>Critical care</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>Depolarization</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Doxorubicin</subject><subject>Drug delivery</subject><subject>Drug dosages</subject><subject>Female</subject><subject>Gene expression</subject><subject>Glutathione</subject><subject>Glycolysis</subject><subject>Gynecological cancer</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Lysates</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Nude</subject><subject>Mitochondria</subject><subject>Molecular weight</subject><subject>Multiple myeloma</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Oxidative stress</subject><subject>Pathology</subject><subject>Peptides</subject><subject>Physical Sciences</subject><subject>Proteasome inhibitors</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Solid tumors</subject><subject>Toxicity</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Ubiquitin</subject><subject>Ubiquitination</subject><subject>Ubiquitination - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkltv0zAYhiMEYmPwDxBEQkJw0c6OD4lvJlXlVGmwqRxuLZ_SeEriYjuI_ntcmk0N2gXyhS37-d7Pfv1m2XMI5hCV8PzGDb4X7XzrejMHBaEMlQ-yU8hQMaMFQA-P1ifZkxBuACCoovRxdoIwAZQgcJpdLxvrRWvjLhe9zkXYdZ2JfpfbXnkjgsljY_Kti6ZXu9zVuUqY1SKafPFu_Rmer6-_QJToxkobnQ9Ps0e1aIN5Ns5n2fcP778tP80urz6ulovLmaKsiDNGaIkNUZBBqZmRuhISCSYpQIporYmuNFICUFhjjWFR41JRYWBRFtgwwdBZ9vKgu21d4KMZgRekhBiXGKJErA6EduKGb73thN9xJyz_u-H8hgsfrWoNF-katSRGaFlgUlEJDS0lIRIoLUGpk9bF2G2QndHK9DG5NhGdnvS24Rv3i1cYFSUjSeDNKODdz8GEyDsblGlb0Rs3HO7NYEmrKqGv_kHvf91IbUR6gO1rl_qqvShfJGsZrRjaU_N7qDS06axKyalt2p8UvJ0UJCaa33EjhhD46uv6_9mrH1P29RHbGNHGJrh2iNb1YQriA6i8C8Gb-s5kCPg--Ldu8H3w-Rj8VPbi-IPuim6Tjv4ARjj9WQ</recordid><startdate>20210910</startdate><enddate>20210910</enddate><creator>Anchoori, Ravi K</creator><creator>George, Logan</creator><creator>Tseng, Ssu-Hsueh</creator><creator>Lam, Brandon</creator><creator>Polkampally, Srinidhi</creator><creator>Amiano, Anjali D</creator><creator>Foran, Palmer</creator><creator>Tsingine, Hannah</creator><creator>Samanapally, Harideep</creator><creator>Carrizo Velasquez, Fernanda</creator><creator>Das, Samarjit</creator><creator>Xing, Deyin</creator><creator>Bin Salam, Ahmad</creator><creator>Karanam, Balasubramanyam</creator><creator>Hung, Chien-Fu</creator><creator>Roden, Richard B S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-1800-8644</orcidid><orcidid>https://orcid.org/0000-0002-2506-0195</orcidid></search><sort><creationdate>20210910</creationdate><title>Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors</title><author>Anchoori, Ravi K ; George, Logan ; Tseng, Ssu-Hsueh ; Lam, Brandon ; Polkampally, Srinidhi ; Amiano, Anjali D ; Foran, Palmer ; Tsingine, Hannah ; Samanapally, Harideep ; Carrizo Velasquez, Fernanda ; Das, Samarjit ; Xing, Deyin ; Bin Salam, Ahmad ; Karanam, Balasubramanyam ; Hung, Chien-Fu ; Roden, Richard B S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-95674e5c191bd9ebd8ab3a9b603c5ddd5d8d3ca061f4d412f47c6ae12724e9a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Analogs</topic><topic>Analysis</topic><topic>Anesthesiology</topic><topic>Animals</topic><topic>Annexin V</topic><topic>Antibodies</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Asymmetry</topic><topic>Benzylidene Compounds - chemistry</topic><topic>Benzylidene Compounds - pharmacology</topic><topic>Binding</topic><topic>Biology and Life Sciences</topic><topic>Bioluminescence</topic><topic>Biomarkers</topic><topic>Bortezomib</topic><topic>BRCA2 protein</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemical bonds</topic><topic>Chirality</topic><topic>Cisplatin</topic><topic>Clustering</topic><topic>Critical care</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>Depletion</topic><topic>Depolarization</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Doxorubicin</topic><topic>Drug delivery</topic><topic>Drug dosages</topic><topic>Female</topic><topic>Gene expression</topic><topic>Glutathione</topic><topic>Glycolysis</topic><topic>Gynecological cancer</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Lysates</topic><topic>Medical research</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Nude</topic><topic>Mitochondria</topic><topic>Molecular weight</topic><topic>Multiple myeloma</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Ovarian cancer</topic><topic>Ovarian carcinoma</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Oxidative stress</topic><topic>Pathology</topic><topic>Peptides</topic><topic>Physical Sciences</topic><topic>Proteasome inhibitors</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Solid tumors</topic><topic>Toxicity</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><topic>Ubiquitin</topic><topic>Ubiquitination</topic><topic>Ubiquitination - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anchoori, Ravi K</creatorcontrib><creatorcontrib>George, Logan</creatorcontrib><creatorcontrib>Tseng, Ssu-Hsueh</creatorcontrib><creatorcontrib>Lam, Brandon</creatorcontrib><creatorcontrib>Polkampally, Srinidhi</creatorcontrib><creatorcontrib>Amiano, Anjali D</creatorcontrib><creatorcontrib>Foran, Palmer</creatorcontrib><creatorcontrib>Tsingine, Hannah</creatorcontrib><creatorcontrib>Samanapally, Harideep</creatorcontrib><creatorcontrib>Carrizo Velasquez, Fernanda</creatorcontrib><creatorcontrib>Das, Samarjit</creatorcontrib><creatorcontrib>Xing, Deyin</creatorcontrib><creatorcontrib>Bin Salam, Ahmad</creatorcontrib><creatorcontrib>Karanam, Balasubramanyam</creatorcontrib><creatorcontrib>Hung, Chien-Fu</creatorcontrib><creatorcontrib>Roden, Richard B S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anchoori, Ravi K</au><au>George, Logan</au><au>Tseng, Ssu-Hsueh</au><au>Lam, Brandon</au><au>Polkampally, Srinidhi</au><au>Amiano, Anjali D</au><au>Foran, Palmer</au><au>Tsingine, Hannah</au><au>Samanapally, Harideep</au><au>Carrizo Velasquez, Fernanda</au><au>Das, Samarjit</au><au>Xing, Deyin</au><au>Bin Salam, Ahmad</au><au>Karanam, Balasubramanyam</au><au>Hung, Chien-Fu</au><au>Roden, Richard B S</au><au>Bera, Soumen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-09-10</date><risdate>2021</risdate><volume>16</volume><issue>9</issue><spage>e0256937</spage><epage>e0256937</epage><pages>e0256937-e0256937</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34506530</pmid><doi>10.1371/journal.pone.0256937</doi><tpages>e0256937</tpages><orcidid>https://orcid.org/0000-0003-1800-8644</orcidid><orcidid>https://orcid.org/0000-0002-2506-0195</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-09, Vol.16 (9), p.e0256937-e0256937 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2571447413 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Analogs Analysis Anesthesiology Animals Annexin V Antibodies Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Asymmetry Benzylidene Compounds - chemistry Benzylidene Compounds - pharmacology Binding Biology and Life Sciences Bioluminescence Biomarkers Bortezomib BRCA2 protein Breast cancer Cancer Cell Line, Tumor Cell Proliferation - drug effects Chemical bonds Chirality Cisplatin Clustering Critical care Cytotoxicity Deoxyribonucleic acid Depletion Depolarization DNA DNA damage DNA repair Doxorubicin Drug delivery Drug dosages Female Gene expression Glutathione Glycolysis Gynecological cancer Health aspects Humans Inhibitors Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Lysates Medical research Medicine and Health Sciences Metabolism Mice Mice, Inbred C57BL Mice, Nude Mitochondria Molecular weight Multiple myeloma NMR Nuclear magnetic resonance Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Oxidative stress Pathology Peptides Physical Sciences Proteasome inhibitors Proteins Research and Analysis Methods Solid tumors Toxicity Tumor cell lines Tumors Ubiquitin Ubiquitination Ubiquitination - drug effects |
| title | Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors |
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