A Potent Small Molecule Sigma1 Modulator Degrades Androgen Receptor In Castration Resistant Prostate Cancer

Many receptors are composed of multiple proteins joined in a complex and are associated with stabilizing proteins Androgen receptors are transcription factors that are associated with a stabilizing protein called Sigma If you effectively inhibit Sigma or otherwise block its function one consequence is that androgen receptor signaling is lost in its entirety Androgen drive is particularly important in prostate cancer For this reason prostate patients who fail to adequately respond to chemo often undergo chemical or surgical castration Castration is helpful to varying degrees however many patients continue to exhibit castration resistant prostate cancer CRPC CRPC occurs because androgen receptors are always signaling even in the absence of testosterone drive i e there is a baseline level of signaling that takes place in the absence of any androgen agonist activity This is called constitutive signaling Contextandapos s drug destabilizes the androgen receptor This destabilization effectively eliminates all signaling including baseline constitutive A key driver of androgen receptor AR signaling in CRPC is the presence of AR variants including splice variants and inhibitor binding mutants which renders abiraterone and enzalutamide the market leading drugs ineffective Targeting Sigma is a novel strategy that inhibits AR signaling regardless of AR variant expression This vastly expands the landscape of men likely to respond to therapy including those with resistance to abiraterone or enzalutamide due to AR variants and provides the opportunity for novel combination therapies Moreover we have already developed and characterized a series of drug like small molecule Sigma modulators that are poised for optimization allowing rapid translation of our preclinical studies to Phase I trials Specific aims of this proposal are Aim To provide an improved drug like Sigma inhibitor suitable for advancement as a Preclinical Candidate The lead compound CT is an orally bioavailable small molecule that potently binds Sigma and induces tumor regression in vivo however CT is not a Preclinical Candidate PCC due to hERG channel inhibition and modest plasma exposure We seek to optimize CT using medicinal chemistry approaches to maintain potency while improving selectivity and optimizing in vitro pharmacokinetic and ADMET properties The resulting optimized lead from this aim will be evaluated for in vivo pharmacokinetics and Day toxicology in mice Aim To establish the in vivo efficacy of an improved Sigma inhibitor in a model of CRPC We will evaluate the improved Sigma modulator in CRPC cell lines C Rv that reflect key hallmarks of CRPC including AR overexpression and constitutively active AR variants The ability of our improved Sigma modulator to inhibit tumor progression will be evaluated in addition to markers of target engagement and disruption of the AR axis These studies directly respond to the overarching challenge of developing effective treatments and addressing mechanisms of resistance This proposal will provide a potent novel small molecule active in vivo at nanomolar concentrations as a potential new therapeutic agent for the benefit of advanced prostate cancer patients and establish the role of a new therapeutic target in castration resistance A pre clinical agent resulting from this work will have significant impact as a potential agent for castration resistant disease