We are pursuing creative efforts to develop therapies urgently needed to treat prostate cancers that become resistant to new anti-androgen therapies. Our approach combines innovations in chemical synthesis with expertise in androgen receptor signaling and prostate cancer. This will allow us to discover a new family of therapeutic agents that combat castration resistant prostate cancer (CRPC) through a unique mode of action that blocks androgen receptor (AR) activity. Indeed, we have developed a new strategy to inhibit the activity of AR by disrupting AR dimerization by displaying AR ligands upon a molecular scaffold. AR dimerization has only been recently recognized as key to determinant to AR activity, and we have developed a novel and facile cell free AR dimerization assay to rapidly test the for effects of the peptoid conjugates on disrupting AR dimerization. We have pioneered an effective method for generating ?peptoid? oligomers that incorporate ligands precisely located along the molecular backbone. Our concept is that the conjugates with high affinity ligands for AR will facilitate receptor binding and block AR dimerization more potently and at lower concentrations than low affinity ligands for AR. This has the potential to be exploited to promote an anti-tumor response by targeting AR in a different way than current AR- directed therapies, making this therapeutic strategy conceptually novel and highly innovative. !
The goal of this proposal is to identify peptoid conjugates that potently inhibit AR dimerization and block AR activity using a spectrum of in vitro and in vivo pre-clinical models of prostate cancer, including a mouse xenograft model, and human prostate cancer organ cultures derived from radical prostatectomies. This comprehensive approach will yield high value compounds suitable for rapid translation to the clinic and first-in- class human trials.
