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1. Figures S20-S23 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

H3B-5942 in combination with palbocyclib shows synergy in vitro and in vivo

Published
2023
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2. Supplementary Methods from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

Additional methods provided.

Published
2023
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3. Figures S13-S19 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

H3B-5942 exhibits dose-dependent inhibition of ER target genes and shows significant efficacy ER Wt and mutant in vivo models

Published
2023
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4. Figures S11-S12 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

H3B-5942 suppresses co-activator recruitment and shows potency in endocrine sensitive and resistant lines

Published
2023
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5. Figures S1-S6 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

ESR1 mutants are resistant to endocrine therapies in vitro and in vivo and H3B-5942 can suppress ER pathway activity.

Published
2023
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6. Supplementary Figure from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Author

Manav Korpal, Ping Zhu, Sudeep Prajapati, Guo Zhu Zheng, Nicholas Larsen, David M. Bolduc, Frédéric H. Vaillancourt, Hao Zeng, Xun Zhang, Shihua Yao, Michael J. Wick, Tarek Sahmoud, Victoria Rimkunas, Tuong-Vi Nguyen, Karthikeyan Murugesan, Alyssa D. Moriarty, Meagan Montesion, Amy Kim, Sean Irwin, Ming-Hong Hao, Lee A. Albacker, Kiran B. Aithal, Deepti Banka, Zhenhua J. Wu, Zhaojie Zhang, Xiaoling Puyang, and Craig Furman

Abstract

Supplementary Figure from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Published
2023
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7. Figures S7-S10 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

C530 residue is critical for H3B-5942 potency

Published
2023
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8. Supplementary Data from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Author

Manav Korpal, Ping Zhu, Sudeep Prajapati, Guo Zhu Zheng, Nicholas Larsen, David M. Bolduc, Frédéric H. Vaillancourt, Hao Zeng, Xun Zhang, Shihua Yao, Michael J. Wick, Tarek Sahmoud, Victoria Rimkunas, Tuong-Vi Nguyen, Karthikeyan Murugesan, Alyssa D. Moriarty, Meagan Montesion, Amy Kim, Sean Irwin, Ming-Hong Hao, Lee A. Albacker, Kiran B. Aithal, Deepti Banka, Zhenhua J. Wu, Zhaojie Zhang, Xiaoling Puyang, and Craig Furman

Abstract

Supplementary Data from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Published
2023
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9. Tables S3-S4 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

Enriched GSEA pathways

Published
2023
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10. Tables S1-S2 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Manav Korpal, Ping Zhu, Peter G. Smith, Markus Warmuth, Lihua Yu, Shihua Yao, Michael J. Wick, Suzanne Wardell, John Wang, Frédéric H. Vaillancourt, Michael Thomas, Vanitha Subramanian, Sasirekha Sivakumar, Amy Siu, Ricardo Ribas, Nathalie Rioux, Victoria Rimkunas, Dominic J. Reynolds, Sujatha Rajagopalan, Sudeep Prajapati, Sunil Pancholi, Morgan O'Shea, John Norris, Tuong-Vi Nguyen, Alyssa Moriarty, Diana Melchers, Lesley-Ann Martin, Crystal Mackenzie, Nicholas Larsen, Weidong G. Lai, Galina Kuznetsov, Pavan Kumar, Namita Kumar, Amy Kim, Craig Karr, Jaya J. Joshi, Sean Irwin, René Houtman, Andrew Hart, Ming-Hong Hao, Peter Fekkes, Sean Eckley, Subhasree Das, Benjamin Caleb, Silvia Buonamici, David M. Bolduc, Sergei Agoulnik, Kiran Aithal, Deepti Banka, Zhenhua J. Wu, Guo Zhu Zheng, Craig Furman, and Xiaoling Puyang

Abstract

Crystallography and amino acid coordinates

Published
2023
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11. Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Author

Craig Furman, Xiaoling Puyang, Zhaojie Zhang, Zhenhua J. Wu, Deepti Banka, Kiran B. Aithal, Lee A. Albacker, Ming-Hong Hao, Sean Irwin, Amy Kim, Meagan Montesion, Alyssa D. Moriarty, Karthikeyan Murugesan, Tuong-Vi Nguyen, Victoria Rimkunas, Tarek Sahmoud, Michael J. Wick, Shihua Yao, Xun Zhang, Hao Zeng, Frédéric H. Vaillancourt, David M. Bolduc, Nicholas Larsen, Guo Zhu Zheng, Sudeep Prajapati, Ping Zhu, and Manav Korpal

Subjects
Clinical Trials as Topic, Cancer Research, Indazoles, Oncology, Pyridines, Estrogen Receptor alpha, Humans, Breast Neoplasms, Female, Neoplasm Recurrence, Local, Fulvestrant
Abstract

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.

Published
2022
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12. Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Author

Sean Eckley, Markus Warmuth, Ping Zhu, Deepti Banka, Zhenhua J. Wu, Nicholas A. Larsen, Sudeep Prajapati, Ricardo Ribas, Ming-Hong Hao, Pavan Kumar, Pete Smith, Michael J. Wick, Kiran Aithal, Crystal Mackenzie, John D. Norris, Sasirekha Sivakumar, V. Subramanian, Tuong-Vi Nguyen, Lihua Yu, Sean Irwin, Andrew Hart, Craig Furman, Alyssa Moriarty, Amy Kim, Benjamin Caleb, O'shea Morgan Welzel, Craig Karr, Sunil Pancholi, Frédéric H. Vaillancourt, Silvia Buonamici, Manav Korpal, Namita Kumar, Weidong G. Lai, Diana Melchers, Peter Fekkes, René Houtman, Lesley-Ann Martin, Xiaoling Puyang, Victoria Rimkunas, Michael Thomas, Amy Siu, Reynolds Dominic, Sujatha Rajagopalan, Suzanne E. Wardell, John Wang, Jaya Julie Joshi, Zheng Guo Zhu, David M. Bolduc, Nathalie Rioux, Subhasree Das, Sergei Agoulnik, Shihua Yao, and Galina Kuznetsov

Subjects
0301 basic medicine, Fulvestrant, Cell growth, business.industry, Estrogen receptor, Cancer, medicine.disease, Estrogen Receptor Antagonists, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Breast cancer, Oncology, In vivo, 030220 oncology & carcinogenesis, Cancer research, medicine, business, Estrogen receptor alpha, medicine.drug
Abstract

Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs. Significance: Nearly 30% of endocrine therapy–resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176–93. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047

Published
2018
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