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

许多受体是由多个蛋白质组成的复合体，它们与“稳定”有关。 蛋白质。雄激素受体是一种转录因子，与一种名为 西格玛1。如果你有效地抑制了Sigma 1(或以其他方式阻断了它的功能)，一个后果是雄激素 受体信号完全丢失。雄激素驱动在前列腺癌中尤为重要。为了这个 原因：对化疗反应不充分的前列腺癌患者通常会接受化疗或手术。 阉割。去势有不同程度的帮助；然而，许多患者继续表现出去势。 耐药前列腺癌(CRPC)。CRPC的发生是因为雄激素受体总是发出信号--即使在 缺乏睾丸素驱动(即，在没有睾丸激素驱动的情况下，信号有一个基线水平 任何雄激素激动剂活性)。这就是所谓的“构成”信号。Context的药物破坏雄激素的稳定 受体。这种不稳定有效地消除了所有信号，包括基线/构成信号。 CRPC中雄激素受体(AR)信号的一个关键驱动因素是AR变异体的存在，包括Splice 变异体和抑制物结合突变体，使阿比特龙和苯扎鲁胺成为市场领先药物 效果不佳。靶向Sigma1是一种新的策略，它抑制AR信号转导，而不考虑AR变体的表达。 这极大地扩大了可能对治疗有反应的男性的范围，包括那些对 阿比特龙或苯扎鲁胺由于AR变异而产生，并为新的联合疗法提供了机会。 此外，我们已经开发并表征了一系列类药物小分子Sigma1 即将进行优化的调节器，允许将我们的临床前研究快速转化为I期试验。 这项建议的具体目标是： 目的1：提供一种适用于临床前研究的改进的类药物Sigma1抑制剂 候选人。先导化合物CT-110是一种口服生物可用小分子，可以有效地结合Sigma1 并在体内诱导肿瘤消退；然而，由于HERG，CT-110不是临床前候选(PCC) 通道抑制和适度的血浆暴露。我们寻求使用药物化学来优化CT-110 在提高选择性的同时保持效力并优化体外药代动力学和 ADMET属性。从这一目标得到的优化的铅将被用于体内药代动力学评估。 和小鼠的7天毒理学。 目的：建立改良的Sigma1抑制剂在慢性前列腺癌模型中的体内疗效。我们会 在CRPC细胞系(C4-2、22Rv1)中评估反映CRPC关键特征的改进的Sigma1调节器， 包括AR过表达和结构性活性AR变异体。我们改进的Sigma1的能力 将评估抑制肿瘤进展的调节剂，以及靶点结合和 AR轴的破坏。 这些研究直接回应了开发有效治疗方法和解决 抗性机制。

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.