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 Sigma1. If you effectively inhibit Sigma 1 (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. Context'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 Sigma1 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 Sigma1 modulators that are poised for optimization, allowing rapid translation of our preclinical studies to Phase I trials. Specific aims of this proposal are: Aim 1: To provide an improved drug-like Sigma1 inhibitor suitable for advancement as a Preclinical Candidate. The lead compound, CT-110, is an orally bioavailable small molecule that potently binds Sigma1 and induces tumor regression in vivo; however, CT-110 is not a Preclinical Candidate (PCC) due to hERG channel inhibition and modest plasma exposure. We seek to optimize CT-110 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 7-Day toxicology in mice. Aim 2: To establish the in vivo efficacy of an improved Sigma1 inhibitor in a model of CRPC. We will evaluate the improved Sigma1 modulator in CRPC cell lines (C4-2, 22Rv1) that reflect key hallmarks of CRPC, including AR overexpression and constitutively active AR variants. The ability of our improved Sigma1 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.