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Your search keyword '"Michael J. Moon"' showing total 3 results
Start Over Author "Michael J. Moon" Topic drug discovery
3 results on '"Michael J. Moon"'

1. Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft

Author

Karensa L. Douglas, Kyoung-Jin Lee, Johnny Y. Nagasawa, Anna Aparicio, Nhin Lu, Andiliy G. Lai, Joshua A. Kaufman, Mehmet Kahraman, Celine Bonnefous, John Sensintaffar, Jeffrey H. Hager, James Joseph, Steven P. Govek, Peter J. Rix, Michael J. Moon, Rene Prudente, Katherine L. Grillot, Julien Jackaline D, Beatrice Darimont, and Nicholas D. Smith

Subjects
Selective Estrogen Receptor Modulators, Indazoles, Cell Survival, Clinical Biochemistry, Pharmaceutical Science, Estrogen receptor, Antineoplastic Agents, 01 natural sciences, Biochemistry, Tamoxifen resistant, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Breast cancer, Drug Discovery, medicine, Tumor regression, Animals, Structural motif, Molecular Biology, Cell Proliferation, Indazole, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Organic Chemistry, Mammary Neoplasms, Experimental, medicine.disease, 0104 chemical sciences, Tamoxifen, 010404 medicinal & biomolecular chemistry, Receptors, Estrogen, chemistry, Cinnamates, Drug Resistance, Neoplasm, Cancer research, Molecular Medicine, Female, Drug Screening Assays, Antitumor
Abstract

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.

Published
2019
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2. Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft

Author

Karensa L. Douglas, Steven P. Govek, Jeffrey H. Hager, Andiliy G. Lai, Nhin Lu, Joshua A. Kaufman, Mehmet Kahraman, Johnny Y. Nagasawa, Rene Prudente, Anna Aparicio, James Joseph, Kyoung-Jin Lee, Nicholas D. Smith, Peter J. Rix, Beatrice Darimont, John Sensintaffar, Celine Bonnefous, Michael J. Moon, and Katherine L. Grillot

Subjects
Indazoles, Clinical Biochemistry, Pharmaceutical Science, Estrogen receptor, Antineoplastic Agents, Breast Neoplasms, Pharmacology, Biochemistry, Tamoxifen resistant, chemistry.chemical_compound, Structure-Activity Relationship, Breast cancer, In vivo, Drug Discovery, medicine, Tumor regression, Animals, skin and connective tissue diseases, Molecular Biology, Indazole, Chemistry, Organic Chemistry, medicine.disease, Xenograft Model Antitumor Assays, In vitro, Rats, Tamoxifen, Cinnamates, Drug Resistance, Neoplasm, Molecular Medicine, Female, Estrogen Receptor Antagonists, Antagonism
Abstract

Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

Published
2015

3. Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts

Author

Johnny Y. Nagasawa, John Sensintaffar, Josh Kaufman, Rene Prudente, Richard A. Heyman, Gang Shao, Steven P. Govek, Jackie Julien, Jeffrey H. Hager, Kyoung-Jin Lee, Kate Grillot, Anna Aparicio, Peter J. Rix, Daniel Brigham, Nicholas D. Smith, Beatrice Darimont, Jing Qian, Andiliy G. Lai, Mehmet Kahraman, Nhin Lu, Karensa L. Douglas, Celine Bonnefous, Michael J. Moon, and James Joseph

Subjects
Selective Estrogen Receptor Modulators, Estrogen receptor, Administration, Oral, Antineoplastic Agents, Breast Neoplasms, Drug resistance, Pharmacology, Small Molecule Libraries, Mice, Breast cancer, Dogs, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Breast, Aromatase, Receptor, Fulvestrant, biology, Chemistry, Estrogen Receptor alpha, medicine.disease, Rats, Tamoxifen, Drug Resistance, Neoplasm, Proteolysis, biology.protein, Molecular Medicine, Heterografts, Female, Estrogen receptor alpha, medicine.drug
Abstract

Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

Published
2015

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