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Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists. 2023
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Natalie Cureton, and
Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
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 ERĪ± 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.
Related Publications
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Natalie Cureton, and
Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
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Darren Stead, and
Bernard Barlaam, and
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Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
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Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
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Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
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Radoslaw Polanski, and
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Haixia Wang, and
Nicky Whalley, and
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Ye Wu, and
Bin Yang, and
Wenzhan Yang
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Bernard Barlaam, and
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Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
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Mandy Lawson, and
Andrew S Lister, and
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Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
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Ryan D Greenwood, and
Sudhir Hande, and
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Thomas A Hunt, and
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Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
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Radoslaw Polanski, and
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James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
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Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
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J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
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Bioorganic & medicinal chemistry letters,
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Natalie Cureton, and
Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
September 2007,
Bioorganic & medicinal chemistry letters,
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Natalie Cureton, and
Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
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Bioorganic & medicinal chemistry letters,
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
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Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
April 2017,
Journal of medicinal chemistry,
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Natalie Cureton, and
Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
April 2023,
Journal of medicinal chemistry,
James S Scott, and
Darren Stead, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Natalie Cureton, and
Paul R J Davey, and
David I Fisher, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Samantha J Hughes, and
Thomas A Hunt, and
Tony Johnson, and
Stefan L Kavanagh, and
Teresa C M Klinowska, and
Carrie J B Larner, and
Mandy Lawson, and
Andrew S Lister, and
David Longmire, and
Stacey Marden, and
Thomas M McGuire, and
Caroline McMillan, and
Lindsay McMurray, and
Christopher J Morrow, and
J Willem M Nissink, and
Thomas A Moss, and
Daniel H O'Donovan, and
Radoslaw Polanski, and
Stephen Stokes, and
Kumar Thakur, and
Dawn Trueman, and
Caroline Truman, and
Michael J Tucker, and
Haixia Wang, and
Nicky Whalley, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
June 2023,
Journal of medicinal chemistry,
