AKR1C3 Inhibitors as Chemotherapeutic Potentiators

醛酮还原酶1 C3(AKR1C3)在一系列白血病、前列腺癌和其他疾病中过表达 在癌症中，它的功能是调节髓系和淋巴母细胞的分化、增殖和凋亡， 合成有效的雄激素，推动癌症的进展，并导致多种疾病的耐药性 化疗药物的类别。我们的初步结果已经确定了最具选择性的AKR1C3亚型 有报道过的抑制剂。这些抑制剂提供显著的增强效应(最高可达208倍) 6种不同类型急性髓系白血病(AML)和去势耐受前列腺的化疗药物种类 癌症(CRPC)细胞系和原发复发患者来源的T细胞急性淋巴细胞白血病(T-ALL) 细胞。我们假设，通过合理设计的小分子对AKR1C3的异构体选择性抑制将 对增强临床化疗药物的细胞毒性有显著效果 恶性肿瘤。这项提议的目标是优化这一新的脚手架，以获得更大的效力、稳定性和 增强效应，以表征AKR1C3在癌症中的作用，并验证AKR1C3亚型是一种 AML、T-ALL和CRPC的治疗靶点。 这一提议的总体影响是体内概念验证，即亚型选择性AKR1C3 抑制剂增加临床化疗的治疗窗口；提高疗效，对抗 抵抗和减少副作用。从而使临床批准的抗癌药物在 脆弱的儿科和老年病患者。

Aldo-keto reductase 1 C3 (AKR1C3) is overexpressed in a range of leukemias, prostate and other cancers, where it functions to regulate myeloid and lymphoblast cell differentiation, proliferation and apoptosis, synthesize potent androgens that drive cancer progression and contributes to drug resistance across several classes of chemotherapeutic. Our preliminary results have identified the most selective AKR1C3 isoform inhibitors ever reported. These inhibitors provide significant potentiation effect (up to 208-fold) across four classes of chemotherapeutics in six different acute myeloid leukemia (AML) and castration-resistant prostate cancer (CRPC) cell lines, and in primary relapsed patient-derived T-cell acute lymphoblastic leukemia (T-ALL) cells. We hypothesize that isoform selective inhibition of AKR1C3 by rationally designed small molecules will have significant effect to potentiate the cytotoxicity of clinical chemotherapeutics across a range of malignancies. The goal of this proposal is to optimize this new scaffold for greater potency, stability and potentiation effect, to characterize the role of AKR1C3 in cancer, and to validate the AKR1C3 isoform as a target for the treatment of AML, T-ALL and CRPC. The overall impact of this proposal is the in vivo proof-of-concept that isoform selective AKR1C3 inhibitors enhance the therapeutic window of clinical chemotherapeutics; enhancing efficacy, countering resistance and reducing side effects. Thus enabling the use of clinically approved anticancer agents in vulnerable pediatric and geriatric patients.