ABSTRACT
Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening â¼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.
Subject(s)
DNA/chemistry , Estrogen Receptor alpha/metabolism , Small Molecule Libraries/chemistry , Animals , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Click Chemistry , DNA/metabolism , Estrogen Antagonists/chemistry , Estrogen Antagonists/metabolism , Estrogen Antagonists/pharmacology , Estrogen Antagonists/therapeutic use , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/genetics , Female , Half-Life , Humans , Indoles/chemistry , Indoles/metabolism , Kinetics , Mice , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence. Two new synthetic approaches to the dihydrothiazine ring system were explored, the first involving a novel trifluoroacetylative-detrifluoroacetylative Pummerer-type reaction sequence and the second involving direct dehydrogenation of tetrahydrothiopyran S,S-dioxide intermediates. Final analogs such as 4 and 13 represent oxidized congeners of recent pre-clinical and clinical oxazolidinones.
