Discovery of ZN-c5, an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) with Improved Pharmacokinetics

Here, we report our strategy to design an optimized oral selective estrogen receptor degrader (SERD), including human pharmacokinetics, by exploiting the bicyclo[1.1.1]pentane (BCP) ring system. The BCP has been shown to serve as a surrogate for phenyl rings and alkyl groups in drug candidates, reducing metabolism and improving physicochemical properties. It has not been extensively profiled in human clinical trials. We optimized a number of molecules and ultimately selected compound 4, which showed excellent cell potency in breast cancer lines and displayed highly favorable in vitro ADME properties across multiple species. This translated into highly desired exposure in vivo across both rodent and nonrodent species exceeding that observed with other contemporary SERDs and downregulators. After fully profiling the compound, we nominated compound 4 (ZN-c5) for clinical development. Compound 4 advanced into Phase 1/2 clinical trials, which demonstrated high human exposure upon dosing patients with 50 mg once a day.