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Discovery of a potent and orally bioavailable zwitterionic series of selective estrogen receptor degrader-antagonists

DOI: 10.1021/acs.jmedchem.2c01964 DOI Help

Authors: James S. Scott (AstraZeneca) , Darren Stead (AstraZeneca) , Bernard Barlaam (AstraZeneca) , Jason Breed (AstraZeneca) , Rodrigo J. Carbajo (AstraZeneca) , Elisabetta Chiarparin (AstraZeneca) , Natalie Cureton (AstraZeneca) , Paul R. J. Davey (AstraZeneca) , David I. Fisher (AstraZeneca) , Eric T. Gangl (AstraZeneca) , Tyler Grebe (AstraZeneca) , Ryan D. Greenwood (AstraZeneca) , Sudhir Hande (AstraZeneca) , Holia Hatoum-Mokdad (AstraZeneca) , Samantha J. Hughes (AstraZeneca) , Thomas A. Hunt (AstraZeneca) , Tony Johnson (AstraZeneca) , Stefan L. Kavanagh (AstraZeneca) , Teresa C. M. Klinowska (AstraZeneca) , Carrie J. B. Larner (AstraZeneca) , Mandy Lawson (AstraZeneca) , Andrew S. Lister (AstraZeneca) , David Longmire (AstraZeneca) , Stacey Marden (AstraZeneca) , Thomas M. Mcguire (AstraZeneca) , Caroline Mcmillan (AstraZeneca) , Lindsay Mcmurray (AstraZeneca) , Christopher J. Morrow (AstraZeneca) , J. Willem M. Nissink (AstraZeneca) , Thomas A. Moss (AstraZeneca) , Daniel H. O’donovan (AstraZeneca) , Radoslaw Polanski (AstraZeneca) , Stephen Stokes (AstraZeneca) , Kumar Thakur (AstraZeneca) , Dawn Trueman (AstraZeneca) , Caroline Truman (AstraZeneca) , Michael J. Tucker (AstraZeneca) , Haixia Wang (AstraZeneca) , Nicky Whalley (AstraZeneca) , Dedong Wu (AstraZeneca) , Ye Wu (AstraZeneca) , Bin Yang (AstraZeneca) , Wenzhan Yang (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 61

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 20015

Abstract: Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Diamond Keywords: Breast Cancer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 20/02/2023 09:50

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)