Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.
James S ScottDarren SteadBernard BarlaamJason BreedRodrigo J CarbajoElisabetta ChiarparinNatalie CuretonPaul R J DaveyDavid I FisherEric T GanglTyler GrebeRyan D GreenwoodSudhir HandeHolia Hatoum-MokdadSamantha J HughesThomas A HuntTony JohnsonStefan L KavanaghTeresa C M KlinowskaCarrie J B LarnerMandy LawsonAndrew S ListerDavid LongmireStacey MardenThomas M McGuireCaroline McMillanLindsay McMurrayChristopher J MorrowJ Willem M NissinkThomas A MossDaniel H O' DonovanRadoslaw PolanskiStephen StokesKumar ThakurDawn TruemanCaroline TrumanMichael J TuckerHaixia WangNicky WhalleyDedong WuYe WuBin YangWenzhan YangPublished in: Journal of medicinal chemistry (2023)
Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38 . This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.