Steven P. Govek

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

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 selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of 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.

Water-soluble PDE4 inhibitors for the treatment of dry eye.

PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin 18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.

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

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.

Abstract 4757: A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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

Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant 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.

Abstract 5053: Discovery of GDC-0810 a novel, non-steroidal selective estrogen receptor degrader with robust activity in pre-clinical models of endocrine-resistant breast cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA 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

Abstract A37: A novel class of selective estrogen receptor degraders display activity in pre-clinical models of ERα+ ovarian cancer

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.

Abstract A4: A novel class of selective ERα degraders acts as full antagonists/ inverse agonists and displays efficacy in pre-clinical models of endocrine-resistant breast cancer and endometrial cancer

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.

Abstract A7: A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer

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.