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

AbstractNearly 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.

2019-04-15·Cancer Research

Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come

Review

作者: Zhu, Ping ; Furman, Craig ; Korpal, Manav ; Reynolds, Dominic ; Zheng, Guo Z. ; Prajapati, Sudeep ; Hao, Ming-Hong ; Rimkunas, Victoria

AbstractThe development of tamoxifen and subsequent estrogen receptor alpha (ERα) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERα antagonists to increase survival rates, resistance to these therapies is an all-too-common occurrence. The majority of resistant tumors, including those with hotspot mutations in the ligand-binding domain of ERα, remain dependent on ERα signaling, indicating that either a more potent or novel class of antagonist could have clinical benefit. With this thought in mind, we developed a novel ERα antagonist that exhibits enhanced potency due to its ability to covalently target a unique cysteine in ER. This review describes the design of this antagonist, H3B-5942, and discusses opportunities for future improvements, which could reduce the risk of escape mutations to this therapeutic modality.

2018-09-01·Cancer Discovery1区 · 医学

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

1区 · 医学

Article

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

AbstractMutations 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

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