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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. 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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7. 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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8. 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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9. Supplementary Table S2andS3 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

H3B-6527 response in 40 HCC cell lines and 625 cell lines.

Published
2023
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10. Supplementary Legends from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

Legends describing each of the supplementary figures and tables

Published
2023
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11. Supplementary Figure S2 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

RNA-seq analysis of 24 CCLE HCC cell lines.

Published
2023
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12. Supplementary Table S1 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

Crystallographic Data collection and Refinement Statistics.

Published
2023
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13. Supplementary Figure S5andS6 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

Body weight data of H3B-6527 as single agent and in combination

Published
2023
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14. Supplementary Figure S7 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

RNA-seq analysis of TCGA HCC samples.

Published
2023
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15. Supplementary Figure S3andS4 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

H3B-6527 efficacy studies in 30 PDX models show that 10 models are responsive

Published
2023
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16. Supplementary Figure S1 from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

H3B-6527 effects in a HCC cell line Hep3B orthotopic xenografts in female nude mice.

Published
2023
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17. Data from H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Anand Selvaraj, Peter G. Smith, Dominic J. Reynolds, Markus Warmuth, John Wang, Peter Fekkes, Nicholas Larsen, Silvia Buonamici, Ping Zhu, Lihua Yu, Weidong G. Lai, Amy Kim, Nathalie Rioux, Eunice Park, Kun Yu, Takashi Satoh, Raelene Hurley, Crystal MacKenzie, Pavan Kumar, Vanitha Subramanian, Craig Karr, Victoria Rimkunas, Jeremy Wu, Suzanna Bailey, Ming-Hong Hao, Sudeep Prajapati, Kana Ichikawa, Chia-Ling Huang, Jennifer Tsai, Erik Corcoran, Heather Coffey, and Jaya Julie Joshi

Abstract

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1–3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999–7013. ©2017 AACR.

Published
2023
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18. 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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19. H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Author

Suzanna L. Bailey, Pete Smith, Victoria Rimkunas, Raelene Hurley, Kun Yu, Lihua Yu, Craig Karr, Ping Zhu, Markus Warmuth, Reynolds Dominic, Takashi Satoh, Anand Selvaraj, Silvia Buonamici, Jennifer Tsai, Erik Corcoran, Jaya Julie Joshi, Crystal MacKenzie, Chia-Ling Huang, Nicholas A. Larsen, Weidong G. Lai, Nathalie Rioux, Amy Kim, Eunice Park, Pavan Kumar, Peter Fekkes, V. Subramanian, Sudeep Prajapati, John Q. Wang, Kana Ichikawa, Heather Coffey, Jeremy Wu, and Ming-Hong Hao

Subjects
0301 basic medicine, Cancer Research, Carcinoma, Hepatocellular, Mice, Nude, Antineoplastic Agents, Palbociclib, Heterocyclic Compounds, 4 or More Rings, Mice, 03 medical and health sciences, Cell Line, Tumor, medicine, Carcinoma, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 4, Receptor, Mice, Inbred BALB C, business.industry, Liver Neoplasms, Cancer, FGF19, Fibroblast growth factor receptor 4, medicine.disease, Xenograft Model Antitumor Assays, digestive system diseases, Fibroblast Growth Factors, Cell Transformation, Neoplastic, 030104 developmental biology, Oncology, Fibroblast growth factor receptor, Hepatocellular carcinoma, Cancer research, Female, business
Abstract

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1–3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999–7013. ©2017 AACR.

Published
2017
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