AKR1C3 Inhibitors as Chemotherapeutic Potentiators

AKR1C3 抑制剂作为化疗增效剂

基本信息

批准号：
10524243
负责人：
Paul Trippier
金额：
$ 4.97万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10524243
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

项目摘要

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.

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度表达癌症，其功能是调节骨髓细胞和淋巴母细胞的分化、增殖和凋亡，合成有效的雄激素，驱动癌症进展并有助于多种药物的耐药性化疗的类别。我们的初步结果已确定最具选择性的 AKR1C3 亚型抑制剂曾有报道。这些抑制剂在四种药物中提供显着的增强作用（高达 208 倍）六种不同的急性髓性白血病（AML）和去势抵抗性前列腺的化疗药物类别癌症 (CRPC) 细胞系，以及原发性复发性患者源性 T 细胞急性淋巴细胞白血病 (T-ALL) 细胞。我们假设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具有显着效果恶性肿瘤。该提案的目标是优化这种新支架，以获得更大的效力、稳定性和增强效应，表征 AKR1C3 在癌症中的作用，并验证 AKR1C3 亚型作为治疗 AML、T-ALL 和 CRPC 的靶点。该提案的总体影响是亚型选择性 AKR1C3 的体内概念验证抑制剂增强临床化疗的治疗窗；增强功效，对抗抵抗力并减少副作用。从而使临床批准的抗癌药物能够用于易受伤害的儿科和老年患者。