Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function
Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents....
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-11, Vol.65 (22), p.15391-15415 |
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| container_title | Journal of medicinal chemistry |
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| creator | Dobrovolskaite, Aiste Moots, Holly Tantak, Mukund P. Shah, Kunal Thomas, Jenna Dinara, Sharifa Massaro, Chelsea Hershberger, Paul M. Maloney, Patrick R. Peddibhotla, Satyamaheshwar Sugarman, Eliot Litherland, Sally Arnoletti, Juan Pablo Jha, Rajiv Kumar Levens, David Phanstiel, Otto |
| description | Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1–FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency. |
| doi_str_mv | 10.1021/acs.jmedchem.2c01350 |
| format | Article |
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A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1–FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.2c01350</identifier><identifier>PMID: 36382923</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Eflornithine - pharmacology ; RNA, Messenger - genetics ; RNA-Binding Proteins ; Spermidine - metabolism</subject><ispartof>Journal of medicinal chemistry, 2022-11, Vol.65 (22), p.15391-15415</ispartof><rights>2022 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a450t-4cb15b8bf839bec4a6dd21c64e846816206d791b65f145c236c81ffcfb8f56563</citedby><cites>FETCH-LOGICAL-a450t-4cb15b8bf839bec4a6dd21c64e846816206d791b65f145c236c81ffcfb8f56563</cites><orcidid>0000-0001-7101-1311 ; 0000-0001-5381-0507</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.2c01350$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01350$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,778,782,883,2754,27059,27907,27908,56721,56771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36382923$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dobrovolskaite, Aiste</creatorcontrib><creatorcontrib>Moots, Holly</creatorcontrib><creatorcontrib>Tantak, Mukund P.</creatorcontrib><creatorcontrib>Shah, Kunal</creatorcontrib><creatorcontrib>Thomas, Jenna</creatorcontrib><creatorcontrib>Dinara, Sharifa</creatorcontrib><creatorcontrib>Massaro, Chelsea</creatorcontrib><creatorcontrib>Hershberger, Paul M.</creatorcontrib><creatorcontrib>Maloney, Patrick R.</creatorcontrib><creatorcontrib>Peddibhotla, Satyamaheshwar</creatorcontrib><creatorcontrib>Sugarman, Eliot</creatorcontrib><creatorcontrib>Litherland, Sally</creatorcontrib><creatorcontrib>Arnoletti, Juan Pablo</creatorcontrib><creatorcontrib>Jha, Rajiv Kumar</creatorcontrib><creatorcontrib>Levens, David</creatorcontrib><creatorcontrib>Phanstiel, Otto</creatorcontrib><title>Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1–FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.</description><subject>Eflornithine - pharmacology</subject><subject>RNA, Messenger - genetics</subject><subject>RNA-Binding Proteins</subject><subject>Spermidine - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFv0zAcxSMEYmXwDRDycRxS_LcTJz2hbF3HpEnssJ4tx7EbV4ldbKdSvwkfF3ftJrhw8uH_3vPT-2XZZ8BzwAS-CRnm21F1slfjnEgMtMRvshmUBOdFjYu32QxjQnLCCL3IPoSwxRhTIPR9dkEZrcmC0Fn2e2mCdHvlD8hp1NjYe2HNYCRqpOnQUnmzF9HsVUAioKXRw-S8G1XsD4Pz1sTeWIWabjtZGVGzUTYG9NSLiO5tb1oT0Up4tN6F6JUY0e2gxiRB18Z2xm7Qo3dRGYsAXa3W14_wFa2OQcbZj9k7LYagPp3fy2y9un26-ZE__Ly7v2keclGUOOaFbKFs61bXdNEqWQjWdQQkK1RdsBoYwayrFtCyUkNRSkKZrEFrqdtal6xk9DL7fsrdTe1xzdTOi4HvvBmFP3AnDP_3Yk3PN27PAZdAqhpSwtU5wbtfkwqRj2lTNQzCKjcFTipaAVSpT5IWJ6n0LgSv9Os_gPmRKk9U-QtVfqaabF_-7vhqesGYBPgkeLa7yds02f8z_wBU3LR6</recordid><startdate>20221124</startdate><enddate>20221124</enddate><creator>Dobrovolskaite, Aiste</creator><creator>Moots, Holly</creator><creator>Tantak, Mukund P.</creator><creator>Shah, Kunal</creator><creator>Thomas, Jenna</creator><creator>Dinara, Sharifa</creator><creator>Massaro, Chelsea</creator><creator>Hershberger, Paul M.</creator><creator>Maloney, Patrick R.</creator><creator>Peddibhotla, Satyamaheshwar</creator><creator>Sugarman, Eliot</creator><creator>Litherland, Sally</creator><creator>Arnoletti, Juan Pablo</creator><creator>Jha, Rajiv Kumar</creator><creator>Levens, David</creator><creator>Phanstiel, Otto</creator><general>American Chemical Society</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7101-1311</orcidid><orcidid>https://orcid.org/0000-0001-5381-0507</orcidid></search><sort><creationdate>20221124</creationdate><title>Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function</title><author>Dobrovolskaite, Aiste ; Moots, Holly ; Tantak, Mukund P. ; Shah, Kunal ; Thomas, Jenna ; Dinara, Sharifa ; Massaro, Chelsea ; Hershberger, Paul M. ; Maloney, Patrick R. ; Peddibhotla, Satyamaheshwar ; Sugarman, Eliot ; Litherland, Sally ; Arnoletti, Juan Pablo ; Jha, Rajiv Kumar ; Levens, David ; Phanstiel, Otto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a450t-4cb15b8bf839bec4a6dd21c64e846816206d791b65f145c236c81ffcfb8f56563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Eflornithine - pharmacology</topic><topic>RNA, Messenger - genetics</topic><topic>RNA-Binding Proteins</topic><topic>Spermidine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dobrovolskaite, Aiste</creatorcontrib><creatorcontrib>Moots, Holly</creatorcontrib><creatorcontrib>Tantak, Mukund P.</creatorcontrib><creatorcontrib>Shah, Kunal</creatorcontrib><creatorcontrib>Thomas, Jenna</creatorcontrib><creatorcontrib>Dinara, Sharifa</creatorcontrib><creatorcontrib>Massaro, Chelsea</creatorcontrib><creatorcontrib>Hershberger, Paul M.</creatorcontrib><creatorcontrib>Maloney, Patrick R.</creatorcontrib><creatorcontrib>Peddibhotla, Satyamaheshwar</creatorcontrib><creatorcontrib>Sugarman, Eliot</creatorcontrib><creatorcontrib>Litherland, Sally</creatorcontrib><creatorcontrib>Arnoletti, Juan Pablo</creatorcontrib><creatorcontrib>Jha, Rajiv Kumar</creatorcontrib><creatorcontrib>Levens, David</creatorcontrib><creatorcontrib>Phanstiel, Otto</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dobrovolskaite, Aiste</au><au>Moots, Holly</au><au>Tantak, Mukund P.</au><au>Shah, Kunal</au><au>Thomas, Jenna</au><au>Dinara, Sharifa</au><au>Massaro, Chelsea</au><au>Hershberger, Paul M.</au><au>Maloney, Patrick R.</au><au>Peddibhotla, Satyamaheshwar</au><au>Sugarman, Eliot</au><au>Litherland, Sally</au><au>Arnoletti, Juan Pablo</au><au>Jha, Rajiv Kumar</au><au>Levens, David</au><au>Phanstiel, Otto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| ispartof | Journal of medicinal chemistry, 2022-11, Vol.65 (22), p.15391-15415 |
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| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Eflornithine - pharmacology RNA, Messenger - genetics RNA-Binding Proteins Spermidine - metabolism |
| title | Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function |
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