Breast cancer is the most common cancer and second leading cause of cancer death in women. Approximately 70% breast cancers are ER-positive. Standard of care therapies include Selective Estrogen Receptor Modulators (SERMs), such as tamoxifen, and aromatase inhibitors. Despite their initial effectiveness, 20-30% of patients eventually relapse and become resistant. Fulvestrant, a Selective Estrogen Receptor Degrader (SERD) with the endogenous estradiol core and a highly lipophilic side-chain, was approved to treat metastatic disease. However, fulvestrant has limited use due to its poor pharmacokinetic and pharmaceutical properties, requiring the drug to be injected intramuscularly. Herein we report the discovery and optimization that led to the identification of a highly potent SERD with improved pharmacokinetic and pharmaceutical properties. To achieve maximal degradation of ER while maintaining acceptable physiochemical properties, we focused on compounds which carry a basic side-chain. We hypothesized that a SERD with a basic side-chain might be a degrader with the full antagonist profile similar to some SERMs, thus avoiding the partial agonist profile observed for both GDC-0810 and AZD9496 in the uterus of immature rats. Furthermore, compounds were synthesized with a novel tetrahydrocarboline (THC) core. The THC core lacks a phenol moiety, which was previously believed to be critical for optimal binding with ER. We reasoned that removal of phenol might offer an opportunity to achieve acceptable oral exposure which had been a significant challenge for ER binders containing a basic side-chain. The resulting combination of a THC core with basic side-chains yielded prototype molecules with good potency and excellent oral exposure across preclinical species. Guided by computational modeling and by co-crystal structures, we further optimized in vitro potency and ER degradation of the THC analogs, eventually leading to the discovery of GNE-149. GNE-149 showed robust, dose-dependent efficacy in both tamoxifen-sensitive and -resistant xenograft models. Moreover, GNE-149 did not exhibit partial agonist effect in the uterus of immature rats, and was well tolerated up to 100 mg/kg PO QD for 7 days in rats.

Discovery of a highly potent and orally bioavailable selective estrogen receptor degrader (SERD) GNE-149 for ER-positive breast cancer

256th National Meeting (2018)

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