2. Academic Validation
  3. Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

  • J Med Chem. 2017 Apr 13;60(7):2790-2818. doi: 10.1021/acs.jmedchem.6b01468.
Heather E Burks 1,  Tinya Abrams 1,  Christina A Kirby 1,  Jason Baird 1,  Alexander Fekete 1,  Lawrence G Hamann 1,  Sunkyu Kim 1,  Franco Lombardo 1,  Alice Loo 1,  Danuta Lubicka 1,  Kaitlin Macchi 1,  Donald P McDonnell 2,  Yuji Mishina 1,  John D Norris 2,  Jill Nunez 1,  Chitra Saran 1,  Yingchuan Sun 1,  Noel M Thomsen 1,  Chunrong Wang 1,  Jianling Wang 1,  Stefan Peukert 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research , 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 2 Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, North Carolina 27710, United States.
PMID: 28296398 DOI: 10.1021/acs.jmedchem.6b01468
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.

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