2. Academic Validation
  3. Discovery of ZN-c5, an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) with Improved Pharmacokinetics

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

  • J Med Chem. 2025 Jul 24;68(14):14740-14755. doi: 10.1021/acs.jmedchem.5c00887.
Sayee G Hegde 1,  Peter Q Huang 1,  Kevin D Bunker 1,  Chad D Hopkins 1,  Deborah H Slee 1,  Mehmet Kahraman 1,  Joseph Pinchman 1,  Rakesh K Sit 1,  Christian C Lee 1,  Michael Rutgard 1,  Ahmed A Samatar 1,  Jiali Li 1,  Jianhui Ma 1,  Hooman Izadi 1,  Frank Q Han 2,  Alex Chao 2
Affiliations

Affiliations

  • 1 Zentalis Pharmaceuticals, San Diego, California 92121, United States.
  • 2 Structure Based Design, Inc., 7270 Trade Street, Suite 102, San Diego, California 92121, United States.
PMID: 40654307 DOI: 10.1021/acs.jmedchem.5c00887
Abstract

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.

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