AKR1C3 Inhibitors as Chemotherapeutic Potentiators

AKR1C3 抑制剂作为化疗增效剂

• 批准号: 10543778
• 负责人: Paul Trippier
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543778
• 关键词: Acute Myelocytic Leukemia; Acute T Cell Leukemia; Adjuvant; Androgens; Anthracycline; Antineoplastic Agents; Apoptosis; Biological Assay; Body Weight; Bone Marrow Cells; Castration; Cell Differentiation process; Cell Line; Cells; Chemicals; Chemosensitization; Child; Childhood; Clinical; Combined Modality Therapy; Coupled; Credentialing; Cytarabine; Data; Daunorubicin; Development; Drug Kinetics; Drug resistance; Elderly; Endometrial Carcinoma; Enzymes; Etoposide; Goals; Human; In Situ; In Vitro; Incidence; Lead; Leukemic Cell; Libraries; Liver Microsomes; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Maximum Tolerated Dose; Metabolic; Methotrexate; Mus; Myelogenous; Myeloid Cells; Oxidoreductase; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Plasma; Platinum; Population; Production; Prognosis; Proliferating; Property; Prostate; Prostate Cancer therapy; Protein Isoforms; Reporting; Resistance; Role; Solid Neoplasm; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Toxic effect; Translating; Treatment Protocols; acute T-cell lymphoblastic leukemia cell; acute lymphoblastic leukemia cell; acute myeloid leukemia cell; age group; cancer type; castration resistant prostate cancer; cytotoxicity; disorder subtype; drug discovery; drug resistance development; efficacy study; enzalutamide; esterase; experience; high risk; in vitro Model; in vivo; in vivo Model; inhibitor; leukemia; leukemia treatment; lymphoblast; malignant breast neoplasm; molecular modeling; mouse model; nanomolar; novel; overexpression; patient tolerability; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; rational design; relapse patients; resistance mechanism; scaffold; side effect; small molecule; systemic toxicity; tumor progression; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Adjuvant; Androgens; Anthracycline; Antineoplastic Agents; Apoptosis; Biological Assay; Body Weight; Bone Marrow Cells; Castration; Cell Differentiation process; Cell Line; Cells; Chemicals; Chemosensitization; Child; Childhood; Clinical; Combined Modality Therapy; Coupled; Credentialing; Cytarabine; Data; Daunorubicin; Development; Drug Kinetics; Drug resistance; Elderly; Endometrial Carcinoma; Enzymes; Etoposide; Goals; Human; In Situ; In Vitro; Incidence; Lead; Leukemic Cell; Libraries; Liver Microsomes; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Maximum Tolerated Dose; Metabolic; Methotrexate; Mus; Myelogenous; Myeloid Cells; Oxidoreductase; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Plasma; Platinum; Population; Production; Prognosis; Proliferating; Property; Prostate; Prostate Cancer therapy; Protein Isoforms; Reporting; Resistance; Role; Solid Neoplasm; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Toxic effect; Translating; Treatment Protocols; acute T-cell lymphoblastic leukemia cell; acute lymphoblastic leukemia cell; acute myeloid leukemia cell; age group; cancer type; castration resistant prostate cancer; cytotoxicity; disorder subtype; drug discovery; drug resistance development; efficacy study; enzalutamide; esterase; experience; high risk; in vitro Model; in vivo; in vivo Model; inhibitor; leukemia; leukemia treatment; lymphoblast; malignant breast neoplasm; molecular modeling; mouse model; nanomolar; novel; overexpression; patient tolerability; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; rational design; relapse patients; resistance mechanism; scaffold; side effect; small molecule; systemic toxicity; tumor progression

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.

Aldo-Keto还原酶1 C3（AKR1C3）在一系列白血病，前列腺和其他方面过表达 癌症，它起作用以调节髓样和淋巴细胞分化，增殖和凋亡， 合成有效的雄激素，可驱动癌症进展，并在几种 化学治疗类别。我们的初步结果已经确定了最选择性的AKR1C3同工型 抑制剂有报道。这些抑制剂在四个 六种不同的急性髓样白血病（AML）和耐Custatration的前列腺中的化学治疗剂类 癌症（CRPC）细胞系，在原发性复发的患者衍生的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的同工型选择性抑制 具有显着作用，可以增强临床化学治疗剂的细胞毒性 恶性肿瘤。该提案的目的是优化这种新的支架，以提高效力，稳定性和 增强作用，以表征AKR1C3在癌症中的作用，并验证AKR1C3同工型 治疗AML，T-ALL和CRPC的靶标。 该提案的总体影响是同工型选择性AKR1C3的体内概念验证 抑制剂增强了临床化学治疗剂的治疗窗口；增强功效，反击 阻力和减少副作用。因此，可以在临床批准的抗癌剂中使用 脆弱的儿科和老年患者。