title: Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.
abstract: Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Heather E
authors.identifier: 0000-0001-9115-9970
authors.initials: HE
authors.lastname: Burks
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Tinya
authors.initials: T
authors.lastname: Abrams
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Kirby
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Baird
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fekete
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Franco
authors.initials: F
authors.lastname: Lombardo
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Danuta
authors.initials: D
authors.lastname: Lubicka
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Macchi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, North Carolina 27710, United States.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, North Carolina 27710, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Norris
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Nunez
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Chitra
authors.initials: C
authors.lastname: Saran
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Yingchuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Noel M
authors.initials: NM
authors.lastname: Thomsen
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Chunrong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D055808:Drug Discovery; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D059748:Proteolysis / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D044005:Tetrahydroisoquinolines; C036658:acrylic acid