Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)
Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evalua...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-12, Vol.67 (23), p.20933-20965 |
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| creator | Rej, Rohan Kalyan Hu, Biao Chen, Zhixiang Acharyya, Ranjan Kumar Wu, Dimin Metwally, Hoda McEachern, Donna Wang, Yu Jiang, Wei Bai, Longchuan Nishimura, Leticia S Gersch, Christina L. Wang, Meilin Wen, Bo Sun, Duxin Carlson, Kathryn Katzenellenbogen, John A. Xu, Guozhang Zhang, Weihong Wu, Wenxue Priestley, E. Scott Sui, Zhihua Rae, James M. Wang, Shaomeng |
| description | Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile in mice and rats over ARV-471. ERD-12310A attained tumor regression in the ER+, estrogen-dependent MCF-7 breast cancer xenograft model with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1 Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer. |
| doi_str_mv | 10.1021/acs.jmedchem.4c01401 |
| format | Article |
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Scott ; Sui, Zhihua ; Rae, James M. ; Wang, Shaomeng</creator><creatorcontrib>Rej, Rohan Kalyan ; Hu, Biao ; Chen, Zhixiang ; Acharyya, Ranjan Kumar ; Wu, Dimin ; Metwally, Hoda ; McEachern, Donna ; Wang, Yu ; Jiang, Wei ; Bai, Longchuan ; Nishimura, Leticia S ; Gersch, Christina L. ; Wang, Meilin ; Wen, Bo ; Sun, Duxin ; Carlson, Kathryn ; Katzenellenbogen, John A. ; Xu, Guozhang ; Zhang, Weihong ; Wu, Wenxue ; Priestley, E. Scott ; Sui, Zhihua ; Rae, James M. ; Wang, Shaomeng</creatorcontrib><description>Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile in mice and rats over ARV-471. ERD-12310A attained tumor regression in the ER+, estrogen-dependent MCF-7 breast cancer xenograft model with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1 Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c01401</identifier><identifier>PMID: 39585895</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; Cell Proliferation - drug effects ; Drug Discovery ; Estrogen Receptor alpha - metabolism ; Female ; Humans ; MCF-7 Cells ; Mice ; Mice, Nude ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2024-12, Vol.67 (23), p.20933-20965</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a227t-34738f6851794fd98f770a5d31dbb47dec0831209bd5cff30519ad5a15db7a343</cites><orcidid>0000-0003-0904-9137 ; 0000-0002-1562-0216 ; 0000-0002-6406-2126 ; 0009-0007-4526-1588 ; 0000-0001-8390-1143 ; 0000-0002-4691-6490 ; 0000-0003-0914-0010 ; 0000-0002-5979-9350 ; 0000-0002-8782-6950</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.4c01401$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01401$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39585895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rej, Rohan Kalyan</creatorcontrib><creatorcontrib>Hu, Biao</creatorcontrib><creatorcontrib>Chen, Zhixiang</creatorcontrib><creatorcontrib>Acharyya, Ranjan Kumar</creatorcontrib><creatorcontrib>Wu, Dimin</creatorcontrib><creatorcontrib>Metwally, Hoda</creatorcontrib><creatorcontrib>McEachern, Donna</creatorcontrib><creatorcontrib>Wang, Yu</creatorcontrib><creatorcontrib>Jiang, Wei</creatorcontrib><creatorcontrib>Bai, Longchuan</creatorcontrib><creatorcontrib>Nishimura, Leticia S</creatorcontrib><creatorcontrib>Gersch, Christina L.</creatorcontrib><creatorcontrib>Wang, Meilin</creatorcontrib><creatorcontrib>Wen, Bo</creatorcontrib><creatorcontrib>Sun, Duxin</creatorcontrib><creatorcontrib>Carlson, Kathryn</creatorcontrib><creatorcontrib>Katzenellenbogen, John A.</creatorcontrib><creatorcontrib>Xu, Guozhang</creatorcontrib><creatorcontrib>Zhang, Weihong</creatorcontrib><creatorcontrib>Wu, Wenxue</creatorcontrib><creatorcontrib>Priestley, E. Scott</creatorcontrib><creatorcontrib>Sui, Zhihua</creatorcontrib><creatorcontrib>Rae, James M.</creatorcontrib><creatorcontrib>Wang, Shaomeng</creatorcontrib><title>Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile in mice and rats over ARV-471. ERD-12310A attained tumor regression in the ER+, estrogen-dependent MCF-7 breast cancer xenograft model with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1 Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Discovery</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMlOwzAURS0EgjL8AUJewiLleWqSZdWGQUIqqso6cjyUoDQudoroZ_EjfBOmA0tWlp7PvfY7CF0S6BOg5Faq0H9bGK1ezaLPFRAO5AD1iKCQ8Az4IeoBUJrQAWUn6DSENwBghLJjdMJykYksFz30Oa6Dch_Gr7GzuJiOk0gQGGIZsGxx8anMsqtdK5tmjZ9dZ9ouzjWe-M2ksLZWUtVuFfDzdDIbjvDYzL3Uxm_6Qufd3LR4an57nMffX_i6mH5_3ZyjIyubYC525xl6uStmo4fkaXL_OBo-JZLStEsYT1lmB5kgac6tzjObpiCFZkRXFU-1UZDFpSCvtFDWMhAkl1pIInSVSsbZGbre9i69e1-Z0JWLuLFpGtma-OuSEUYzTimDiPItqrwLwRtbLn29kH5dEih_nZfRebl3Xu6cx9jV7oVVFe_-QnvJEYAtsIm7lY82w_-dPws4kAs</recordid><startdate>20241212</startdate><enddate>20241212</enddate><creator>Rej, Rohan Kalyan</creator><creator>Hu, Biao</creator><creator>Chen, Zhixiang</creator><creator>Acharyya, Ranjan Kumar</creator><creator>Wu, Dimin</creator><creator>Metwally, Hoda</creator><creator>McEachern, Donna</creator><creator>Wang, Yu</creator><creator>Jiang, Wei</creator><creator>Bai, Longchuan</creator><creator>Nishimura, Leticia S</creator><creator>Gersch, Christina L.</creator><creator>Wang, Meilin</creator><creator>Wen, Bo</creator><creator>Sun, Duxin</creator><creator>Carlson, Kathryn</creator><creator>Katzenellenbogen, John A.</creator><creator>Xu, Guozhang</creator><creator>Zhang, Weihong</creator><creator>Wu, Wenxue</creator><creator>Priestley, E. 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Scott</au><au>Sui, Zhihua</au><au>Rae, James M.</au><au>Wang, Shaomeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-12-12</date><risdate>2024</risdate><volume>67</volume><issue>23</issue><spage>20933</spage><epage>20965</epage><pages>20933-20965</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile in mice and rats over ARV-471. ERD-12310A attained tumor regression in the ER+, estrogen-dependent MCF-7 breast cancer xenograft model with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1 Y537S mutation, which confers resistance to traditional antiestrogens. 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| subjects | Administration, Oral Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Breast Neoplasms - drug therapy Breast Neoplasms - pathology Cell Proliferation - drug effects Drug Discovery Estrogen Receptor alpha - metabolism Female Humans MCF-7 Cells Mice Mice, Nude Rats Rats, Sprague-Dawley Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα) |
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