AKR1C3 Inhibitors as Chemotherapeutic Potentiators

醛酮还原酶1C 3（AKR 1C 3）在一系列白血病、前列腺和其他肿瘤中过表达。 癌症，其中它的功能是调节骨髓和淋巴母细胞分化、增殖和凋亡， 合成有效雄激素，推动癌症进展，并有助于在几个药物耐药性 化疗的种类。我们的初步结果已经确定了最具选择性的AKR 1C 3亚型 有报道的抑制剂这些抑制剂在四个细胞中提供显著的增强效应（高达208倍）。 六种不同的急性髓细胞白血病（AML）和去势抵抗性前列腺的化疗药物类别 癌症（CRPC）细胞系，以及原发性复发患者来源的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选择性抑制AKR 1C 3亚型， 具有显著的增强临床化疗药物的细胞毒性的作用， 恶性肿瘤。该提案的目标是优化这种新支架，以获得更大的效力、稳定性和 增强作用，以表征AKR 1C 3在癌症中的作用，并验证AKR 1C 3同种型作为一种免疫调节剂。 治疗AML、T-ALL和CRPC的靶点。 该提议的总体影响是同种型选择性AKR 1C 3 抑制剂增强临床化学治疗剂的治疗窗;增强功效，对抗肿瘤， 抵抗力和减少副作用。从而使得临床上批准的抗癌剂能够用于治疗癌症。 脆弱的儿童和老年患者。

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.