AKR1C3 Inhibitors as Chemotherapeutic Potentiators

AKR1C3 抑制剂作为化疗增效剂

• 批准号: 10320383
• 负责人: Paul Trippier
• 金额: $ 37.55万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320383
• 关键词: Acute Lymphocytic Leukemia; 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; Coupled; Cytarabine; Data; Daunorubicin; Development; Disease; 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; Property; Prostate; Prostate Cancer therapy; Protein Isoforms; Reporting; Resistance; Role; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Toxic effect; Translating; Treatment Protocols; acute T-cell lymphoblastic leukemia cell; acute myeloid leukemia cell; age group; base; cancer type; castration resistant prostate cancer; cytotoxicity; drug development; drug discovery; 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 -酮还原酶1C3 （AKR1C3）在一系列白血病、前列腺癌和其他疾病中过度表达