Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor
The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferas...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2020-06, Vol.11 (6), p.1324-1329 |
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| container_title | ACS medicinal chemistry letters |
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| creator | Wilson, Jonathan E. Patel, Gaurav Patel, Chirag Brucelle, Francois Huhn, Annissa Gardberg, Anna S. Poy, Florence Cantone, Nico Bommi-Reddy, Archana Sims, Robert J. Cummings, Richard T. Levell, Julian R. |
| description | The
histone acetyltransferases, CREB binding protein (CBP) and
EP300, are master transcriptional co-regulators that have been implicated
in numerous diseases, such as cancer, inflammatory disorders, and
neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP
histone acetyltransferase (HAT) inhibitor, CPI-1612 or
17
, was developed from the lead compound
3
. Replacement
of the indole scaffold of
3
with the aminopyridine scaffold
of
17
led to improvements in potency, solubility, and
bioavailability. These characteristics resulted in a 20-fold lower
efficacious dose for
17
relative to lead
3
in a JEKO-1 tumor mouse xenograft study. |
| doi_str_mv | 10.1021/acsmedchemlett.0c00155 |
| format | Article |
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histone acetyltransferases, CREB binding protein (CBP) and
EP300, are master transcriptional co-regulators that have been implicated
in numerous diseases, such as cancer, inflammatory disorders, and
neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP
histone acetyltransferase (HAT) inhibitor, CPI-1612 or
17
, was developed from the lead compound
3
. Replacement
of the indole scaffold of
3
with the aminopyridine scaffold
of
17
led to improvements in potency, solubility, and
bioavailability. These characteristics resulted in a 20-fold lower
efficacious dose for
17
relative to lead
3
in a JEKO-1 tumor mouse xenograft study.</description><identifier>ISSN: 1948-5875</identifier><identifier>EISSN: 1948-5875</identifier><identifier>DOI: 10.1021/acsmedchemlett.0c00155</identifier><identifier>PMID: 32551019</identifier><language>eng</language><publisher>American Chemical Society</publisher><subject>Letter</subject><ispartof>ACS medicinal chemistry letters, 2020-06, Vol.11 (6), p.1324-1329</ispartof><rights>Copyright © 2020 American Chemical Society 2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-9c9ceba98b0801bec213fdefb71f7868d3c9f5cf9ff4fcf3751e31cc85a5c2f43</citedby><cites>FETCH-LOGICAL-c391t-9c9ceba98b0801bec213fdefb71f7868d3c9f5cf9ff4fcf3751e31cc85a5c2f43</cites><orcidid>0000-0002-6171-3819 ; 0000-0002-7943-5861</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/PMC7294707/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294707/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,2752,27905,27906,53772,53774</link.rule.ids></links><search><creatorcontrib>Wilson, Jonathan E.</creatorcontrib><creatorcontrib>Patel, Gaurav</creatorcontrib><creatorcontrib>Patel, Chirag</creatorcontrib><creatorcontrib>Brucelle, Francois</creatorcontrib><creatorcontrib>Huhn, Annissa</creatorcontrib><creatorcontrib>Gardberg, Anna S.</creatorcontrib><creatorcontrib>Poy, Florence</creatorcontrib><creatorcontrib>Cantone, Nico</creatorcontrib><creatorcontrib>Bommi-Reddy, Archana</creatorcontrib><creatorcontrib>Sims, Robert J.</creatorcontrib><creatorcontrib>Cummings, Richard T.</creatorcontrib><creatorcontrib>Levell, Julian R.</creatorcontrib><title>Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor</title><title>ACS medicinal chemistry letters</title><description>The
histone acetyltransferases, CREB binding protein (CBP) and
EP300, are master transcriptional co-regulators that have been implicated
in numerous diseases, such as cancer, inflammatory disorders, and
neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP
histone acetyltransferase (HAT) inhibitor, CPI-1612 or
17
, was developed from the lead compound
3
. Replacement
of the indole scaffold of
3
with the aminopyridine scaffold
of
17
led to improvements in potency, solubility, and
bioavailability. These characteristics resulted in a 20-fold lower
efficacious dose for
17
relative to lead
3
in a JEKO-1 tumor mouse xenograft study.</description><subject>Letter</subject><issn>1948-5875</issn><issn>1948-5875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpVkUFrGzEQhUVpadK0f6Ho2EM20axW1qqHguOmjSEQQ9uz0I5HtYq8SiTZ4H_fDTEhOc3AfLyZeY-xzyAuQLRw6bBsaY0b2kaq9UKgEKDUG3YKpusb1Wv19kV_wj6U8k-ImdFavGcnslUKBJhT9vA9FEx7ygeePF-slg3MoP3K53yVKo31nP-iSFjDns65G9f8LrsYD_wqJLd3IbohEr9eSSEuF1crfhNKTSPxOVI9xJrdWDxlV4gvx00YQk35I3vnXSz06VjP2J8f178XN83t3c_lYn7boDRQG4MGaXCmH0QvYCBsQfo1-UGD1_2sX0s0XqE33ncevdQKSAJir5zC1nfyjH170r3fDY9WTc9Mp9v7HLYuH2xywb6ejGFj_6a91a3ptNCTwJejQE4POyrVbievKEY3UtoV23agJrTtzITOnlDMqZRM_nkNCPuYl32dlz3mJf8DHNqNtA</recordid><startdate>20200611</startdate><enddate>20200611</enddate><creator>Wilson, Jonathan E.</creator><creator>Patel, Gaurav</creator><creator>Patel, Chirag</creator><creator>Brucelle, Francois</creator><creator>Huhn, Annissa</creator><creator>Gardberg, Anna S.</creator><creator>Poy, Florence</creator><creator>Cantone, Nico</creator><creator>Bommi-Reddy, Archana</creator><creator>Sims, Robert J.</creator><creator>Cummings, Richard T.</creator><creator>Levell, Julian R.</creator><general>American Chemical Society</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6171-3819</orcidid><orcidid>https://orcid.org/0000-0002-7943-5861</orcidid></search><sort><creationdate>20200611</creationdate><title>Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor</title><author>Wilson, Jonathan E. ; Patel, Gaurav ; Patel, Chirag ; Brucelle, Francois ; Huhn, Annissa ; Gardberg, Anna S. ; Poy, Florence ; Cantone, Nico ; Bommi-Reddy, Archana ; Sims, Robert J. ; Cummings, Richard T. ; Levell, Julian R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-9c9ceba98b0801bec213fdefb71f7868d3c9f5cf9ff4fcf3751e31cc85a5c2f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Letter</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wilson, Jonathan E.</creatorcontrib><creatorcontrib>Patel, Gaurav</creatorcontrib><creatorcontrib>Patel, Chirag</creatorcontrib><creatorcontrib>Brucelle, Francois</creatorcontrib><creatorcontrib>Huhn, Annissa</creatorcontrib><creatorcontrib>Gardberg, Anna S.</creatorcontrib><creatorcontrib>Poy, Florence</creatorcontrib><creatorcontrib>Cantone, Nico</creatorcontrib><creatorcontrib>Bommi-Reddy, Archana</creatorcontrib><creatorcontrib>Sims, Robert J.</creatorcontrib><creatorcontrib>Cummings, Richard T.</creatorcontrib><creatorcontrib>Levell, Julian R.</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wilson, Jonathan E.</au><au>Patel, Gaurav</au><au>Patel, Chirag</au><au>Brucelle, Francois</au><au>Huhn, Annissa</au><au>Gardberg, Anna S.</au><au>Poy, Florence</au><au>Cantone, Nico</au><au>Bommi-Reddy, Archana</au><au>Sims, Robert J.</au><au>Cummings, Richard T.</au><au>Levell, Julian R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor</atitle><jtitle>ACS medicinal chemistry letters</jtitle><date>2020-06-11</date><risdate>2020</risdate><volume>11</volume><issue>6</issue><spage>1324</spage><epage>1329</epage><pages>1324-1329</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><abstract>The
histone acetyltransferases, CREB binding protein (CBP) and
EP300, are master transcriptional co-regulators that have been implicated
in numerous diseases, such as cancer, inflammatory disorders, and
neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP
histone acetyltransferase (HAT) inhibitor, CPI-1612 or
17
, was developed from the lead compound
3
. Replacement
of the indole scaffold of
3
with the aminopyridine scaffold
of
17
led to improvements in potency, solubility, and
bioavailability. These characteristics resulted in a 20-fold lower
efficacious dose for
17
relative to lead
3
in a JEKO-1 tumor mouse xenograft study.</abstract><pub>American Chemical Society</pub><pmid>32551019</pmid><doi>10.1021/acsmedchemlett.0c00155</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-6171-3819</orcidid><orcidid>https://orcid.org/0000-0002-7943-5861</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1948-5875 |
| ispartof | ACS medicinal chemistry letters, 2020-06, Vol.11 (6), p.1324-1329 |
| issn | 1948-5875 1948-5875 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7294707 |
| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ACS Publications; PubMed Central |
| subjects | Letter |
| title | Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor |
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