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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.

[Image: see text] The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.

About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer. DOI: http://dx.doi.org/10.7554/eLife.15828.001

Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway–targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. Cancer Res; 72(6); 1494–503. ©2012 AACR.

Breast cancer is the most frequently diagnosed cancer among women and remains the second leading cause of cancer death in women. An estimated 70% of all breast cancers express estrogen receptor alpha (ERα); and endocrine therapies have validated ERα as a target for the treatment of breast cancer. Despite effective endocrine therapies, many patients eventually relapse and become resistant to standard of care treatments. Endocrine resistant tumors often remain dependent on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor degrader (SERD), fulvestrant. However, fulvestrant may be limited in achieving maximal target occupancy due to pharmaceutical and pharmacokinetics properties which necessitates intramuscular route of administration. Consequently, SERDs with superior drug-like properties were sought to allow consistent and rapid achievement of maximal therapeutic exposure. GDC-0810 and GDC-0927 as first and second generation orally bioavailable SERDs were discovered through a prospective lead optimization on ERα degradation. The evolution from GDC-0810 to GDC-0927 will be described and provides new insights into ERα biology and biochemistry. By shifting away from the acrylic acid moiety in GDC-0810, GDC-0927 achieved increased potency and more consistent, complete suppression of ER signaling. Co-crystal structures of both GDC-0810 and GDC-0927 with ERα will be shared. Subsequent optimization of GDC-0927 resulting in improved pharmacokinetic properties will also be highlighted. Citation Format: Mehmet Kahraman, Steven P. Govek, Johnny Y. Nagasawa, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Lu, KyoungJin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D. Joseph, Beatrice Darimont, Daniel Brigham, Richard Heyman, Peter J. Rix, Jeffrey H. Hager, Nicholas D. Smith, Robert A. Blake, Jae Chang, Edna Choo, Anneleen Daemen, Lori S. Friedman, Jane Guan, Steven Hartman, Ellen Ingalla, James R. Kiefer, Tracy Kleinheinz, Sharada Labadie, Ciara Metcalfe, Vidhi Mody, Michelle Nannini, Deepak Sampath, Amy Young, Maia Vinogradova, Wei Zhou, Jun Liang, Xiaojing Wang. Discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: From GDC-0810 to GDC-0927 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1648.

The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.

The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.

A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1 S ,2 R -isomers. Thus, 15l exhibited IC 50 values of 1.7 nM at NET and 25 nM at SERT, which were, respectively, 20- and 13-fold more potent than 1 S ,2 R -milnacipran 1 – II .

A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.

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.

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.

The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.

The majority of breast cancers express estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can be activated in the absence of estrogens via point mutations in ERα or cellular signaling pathways supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling. Here we disclose the discovery of ARN-810, also known as GDC-0810. ARN-810 is an oral, potent antagonist of ER that also induces degradation of ERα at picomolar concentrations. ARN-810 treatment results in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show ARN-810 induces ERα conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. In vitro, ARN-810 is active on wild-type and the constitutively active ERα mutants found in endocrine resistant breast cancer patients. Importantly, ARN-810 is active in cell-line and in vivo models of ESR1 wild-type and mutant, primary and endocrine-resistant breast cancers including patient derived xenograft (PDX) models. These preclinical data indicate that ARN-810, a novel Selective Estrogen Receptor Degrader (SERD), holds promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. ARN-810 is in clinical development for the treatment of ER+ breast cancer. Citation Format: James Joseph, Steven Govek, Beatrice Darimont, Daniel Brigham, Anna Aparicio, Eric Bischoff, Mehmet Kahraman, Michelle Nannini, Joshua Kaufman, Andily Lai, Kyoung-Jin Lee, Jason Oeh, Nhin Lu, Wei Zhou, Michael Moon, Jing Qian, John Sensintaffar, Gang Shao, Deepak Sampath, Lori S. Friedman, Peter Rix, Richard A. Heyman, Nicholas Smith, Jeffrey H. Hager. Discovery of GDC-0810 a novel, non-steroidal selective estrogen receptor degrader with robust activity in pre-clinical models of endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5053. doi:10.1158/1538-7445.AM2015-5053

80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can be activated in the absence of estrogens via point mutations in ERα or cellular signaling pathways supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling. We have identified two novel series of non-steroidal ERα antagonists, series I exemplified by ARN-810, now in clinical trials for treatment of endocrine resistant breast cancer, and series II, both of which induce degradation of ERα at picomolar concentrations resulting in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show that both series induce ERα conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. In vitro, both ligand series are active on wild-type and the constitutively active ERα mutants found in endocrine resistant breast cancer patients. Importantly, these compounds yield tumor regression in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Based on their unique in vitro profile, and good pharmacokinetics following oral dosing, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. Citation Format: James D. Joseph, Beatrice Darimont, Steven Govek, Dan Brigham, Jing Qian, John Sensintaffar, Gang Shao, Anna Aparicio, Mehmet Kahraman, Andiliy Lai, Kyoung-Jin Lee, Nhin Lu, Johnny Nagasawa, Michael Moon, Peter Rix, Nick Smith, Jeff Hager. A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4757. doi:10.1158/1538-7445.AM2014-4757

Greater than 50% of high grade serous ovarian cancers express the estrogen receptor alpha (ERα). This observation, in addition to multiple lines of epidemiological and preclinical data, suggests that, similar to breast and endometrial cancer, estrogen receptor signaling may play a role in the development and progression of ovarian cancer. Unfortunately, unlike in breast cancer, therapeutically targeting ERα signaling in patients with recurrent ovarian cancer typically yields only marginal clinical responses. However, patient selection based solely on ERα expression increases the response rate of aromatase inhibitors suggesting that ERα may be a viable therapeutic target in a subset of ovarian cancer patients. Given the presentation of late-stage disease, the mutational complexity and alteration of multiple signaling pathways known to induce ligand independent ERα activity in ovarian cancer, additional levels of patient stratification as well as novel therapeutics that target both the ligand dependent and independent ERα signaling, have the potential to yield better therapeutic outcomes. We have identified novel, orally bioavailable non-steroidal ERα antagonists that induce ERα degradation at picomolar concentrations in vitro resulting in significant reduction in steady state ERα protein levels in multiple cancer cell lines. Using peptide-based conformational profiling, we show that these ligands induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. Importantly, these compounds block the growth of tamoxifen-sensitive and -resistant models of breast cancer and endometrial cancer in vivo. Similar to the breast and endometrial cancer models, these compounds antagonize ER target gene expression and induce ERα degradation in two ER+ ovarian cancer cell lines, OVSAHO and OVKATE, whereas the first generation ER antagonist tamoxifen antagonizes transcription but stabilizes ERα in this setting. Consistent with their transcriptional antagonist and degrader activities, these compounds also inhibit the hormone-dependent growth of these cell lines in vivo. Based on these findings, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that may hold promise as a next generation therapy for the treatment of ER+ ovarian cancer as monotherapy and importantly as combination therapy with agents that target the key nodal points critical to malignant progression or new, emergent agents displaying promising activity. Citation Format: James D. Joseph, Beatrice Darimont, Steven Govek, Dan Brigham, Anna Aparicio, Mehmet Kahraman, Andiliy Lai, Kyoung-Jin Lee, Nhin Lu, Johnny Nagasawa, Josh Kaufman, Michael Moon, Rene Prudente, Jing Qian, John Sensintaffar, Gang Shao, Peter Rix, Nick Smith, Jeff Hager. A novel class of selective estrogen receptor degraders display activity in pre-clinical models of ERα+ ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A37.

80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to depend on ERα for growth and survival. The emerging evidence that ERα can signal in both a ligand-dependent and ligand-independent manner supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling. We have identified novel, non-steroidal ERα antagonists that induce degradation of ERα in breast cancer cell lines at picomolar concentrations resulting in significant reduction in steady state ERα protein levels. Using peptide-based conformational profiling, we show that these Selective Estrogen Receptor Degraders (SERDs) induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating a unique mechanism of action. This unique biological profile coupled with good oral pharmacokinetics produces tumor regressions in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Recent pre-clinical and clinical data indicate that PI3K pathway signaling can contribute to the endocrine resistant state. In a preclinical model of tamoxifen resistant breast cancer in which SERD monotherapy only produces tumor growth inhibition, SERD therapy in combination with torc1/2 inhibition results in frank tumor regressions. These orally bioavailable SERDs hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-12.

Eighty percent of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with antihormonal therapies that directly block ERα function (e.g., tamoxifen) or hormone synthesis (aromatase inhibitors). While these therapies are initially effective, acquired resistance invariably emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can signal in the absence of estrogens supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling. We have identified novel, nonsteroidal ERα antagonists that induce degradation of ERα at picomolar concentrations resulting in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show that these ligands induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. Importantly, these compounds yield tumor regression in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Based on their unique in vitro profile, and good pharmacokinetics following oral dosing, these compounds represent a novel class of selective estrogen receptor degraders (SERDs) that hold promise as a next-generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance.

While endocrine therapies are initially effective to treat estrogen receptor (ERα) positive breast cancer tumors, acquired resistance invariably emerges. Although resistant tumors typically display changes in PI3K or other kinase pathways, the majority of these tumors continue to express and depend on ERα for growth and survival. Exploring the hypothesis that endocrine resistance might involve hormone-independent activities of ERα, we have developed two distinct classes of potent, non-steroidal ERα modulators that antagonize hormone-mediated transcriptional activities of ER and lower ERα steady state levels. These compounds showed robust efficacy in pre-clinical models of endocrine-resistant breast cancer, including some with up-regulated PI3K pathways. In contrast to their activity as full antagonists/ inverse agonists in the breast, the two classes of ERα modulators displayed distinct abilities to oppose the activity of estradiol in the uterine endometrium, another well-characterized ERα target tissue. Similar to endocrine-resistant breast cancer, a large percentage of endometrial cancers have altered PI3K pathways and typically respond poorly to endocrine therapy. In mouse xenograft models one of our compounds inhibited the growth of ECC-1 endometrial cancer tumors with substantially higher efficacy than the selective ER modulator arzoxifene, which in a phase II clinical trial exhibited a 30% response rate in patients with recurring ERα-positive endometrial cancers. Hence, beyond their promise as a next generation therapy for the treatment of endocrine resistant ER+ breast cancer, these novel classes of selective estrogen receptor degraders might also open new opportunities for endocrine therapies targeting endometrial cancer.

60–75% of all breast cancers express the estrogen receptor (ER) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to express and depend on ER for growth and survival, suggesting that novel approaches to target ER signaling have tremendous potential to treat endocrine-resistant disease. We have identified novel ER antagonists that induce degradation of ER at picomolar concentrations resulting in significant reduction in steady state ER protein levels in breast cancer cell lines. These compounds yield regression in both Tamoxifen-sensitive and - resistant models of breast cancer in vivo. Based on their unique in vitro profile, good pharmacokinetics and oral bioavailability, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that hold tremendous promise as a next generation therapy for the treatment of ER+ breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A133.