Selective inhibitors to improve CPT-11 therapy

选择性抑制剂改善 CPT-11 治疗

• 批准号: 7992106
• 负责人: PHILIP M POTTER
• 金额: $ 32.4万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992106
• 关键词: Acetylcholinesterase; Adult; Adverse drug effect; Affinity; Animal Model; Animals; Antineoplastic Agents; Bile fluid; Biochemical; Biochemistry; Biological; Butyrylcholinesterase; Camptothecin; Carboxylic Ester Hydrolases; Cell Culture Techniques; Child; Childhood; Cholesterol Esters; Cocaine; Colon Carcinoma; Complex Mixtures; Crystallography; Development; Diarrhea; Dose; Dose-Limiting; Engineering; Enzyme Inhibition; Enzymes; Evaluation; Goals; Half-Life; Heroin; Hour; Human; Hydrolysis; In Vitro; Incidence; Intestines; Knock-in Mouse; Lipids; Liver; Malignant Neoplasms; Meperidine; Metabolism; Methods; Modeling; Mus; Pediatric Neoplasm; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plant Resins; Plasma; Poison; Procaine; Prodrugs; Property; Proteins; Quantitative Structure-Activity Relationship; Reagent; Resistance; Ritalin; SN-38; Severities; Small Intestines; Street Drugs; Testing; Therapeutic; Toxic effect; Type I DNA Topoisomerases; Water; Xenograft procedure; analog; antitumor agent; base; benzil; cancer therapy; carboxylesterase; chemotherapeutic agent; design; esterase; improved; in vivo; inhibitor/antagonist; mouse model; novel; public health relevance; research study; response; small molecule; tumor

DESCRIPTION (provided by applicant): CPT-11 is a highly effective, camptothecin-based anticancer agent that is currently approved for the treatment of colon cancer. This compound is a prodrug and is activated by carboxylesterases to yield SN-38, a potent topoisomerase I poison. The dose limiting toxicity for CPT-11 is delayed diarrhea that occurs 48-96 hours following administration. This is thought to arise, in part, from direct activation of CPT-11, that is secreted in the bile, by a human intestinal carboxylesterase (CE) that is highly expressed in the small intestine. We hypothesize that by inhibiting this enzyme, reduced SN-38 will be produced from drug hydrolysis in the gut, thereby reducing the toxicity associated with CPT-11 treatment. The goals of this application are therefore to develop selective CE inhibitors that can be used to ameliorate the toxicity associated with CPT-11 administration. Highly potent, non-toxic small molecule inhibitors based upon the prototypical compound benzil have been identified, and we propose to develop these agents for use in inhibition of the human intestinal CE (hiCE). NMR, x-ray crystallography, medicinal chemistry, QSAR, biochemical and in vivo approaches will all be employed to validate the efficacy of suitable compounds The specific aims of this application are: 1) to determine the mechanism of CE inhibition by benzil; 2) to develop water-soluble analogues of benzil; 3) to assess the biochemical and biological properties of these compounds; and 4) assess their efficacy at modulating CPT-11-induced toxicity in a plasma esterase-deficient mouse model where hiCE is expressed in the mouse intestine. We believe that, if successful, these studies will provide reagents that can ameliorate the delayed diarrhea associated with CPT-11 administration, and potentially allow dose intensification of the drug. This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent. PUBLIC HEALTH RELEVANCE: These studies will identify and characterize novel drugs that can reduce the toxicity associated with CPT-11 treatment. Since this chemotherapeutic agent is widely used for cancer therapy, any approaches that reduce the side-effects of this drug will be highly desirable. We propose to develop such compounds that should have applicability to a wide variety of malignancies.

描述（由申请人提供）：CPT-11是一种高效的、基于喜树碱的抗癌剂，目前被批准用于治疗结肠癌。该化合物是一种前药，被羧酸酯酶激活产生 SN-38，一种有效的拓扑异构酶 I 毒物。 CPT-11 的剂量限制性毒性是给药后 48-96 小时发生的迟发性腹泻。这被认为部分是由于小肠中高度表达的人肠羧酸酯酶 (CE) 对胆汁中分泌的 CPT-11 的直接激活所致。我们假设通过抑制这种酶，药物在肠道中水解会产生减少的 SN-38，从而减少与 CPT-11 治疗相关的毒性。因此，本申请的目标是开发选择性 CE 抑制剂，可用于改善与 CPT-11 给药相关的毒性。基于原型化合物苯偶酰的高效、无毒小分子抑制剂已被鉴定，我们建议开发这些药物用于抑制人肠道 CE (hiCE)。 NMR、X射线晶体学、药物化学、QSAR、生物化学和体内方法都将用于验证合适化合物的功效。本申请的具体目的是：1）确定苯偶酰抑制CE的机制； 2）开发苯偶酰的水溶性类似物； 3) 评估这些化合物的生化和生物学特性； 4) 评估其在血浆酯酶缺陷小鼠模型中调节 CPT-11 诱导的毒性的功效，其中 hiCE 在小鼠肠道中表达。我们相信，如果成功，这些研究将提供可以改善与 CPT-11 给药相关的迟发性腹泻的试剂，并可能允许加强该药物的剂量。这可能会提高抗肿瘤功效，此外，还可能允许使用这种 CPT-11 来对抗对该药物表现出边际反应的更具耐药性的恶性肿瘤。 公共卫生相关性：这些研究将鉴定和表征可以减少与 CPT-11 治疗相关的毒性的新药。由于这种化疗剂广泛用于癌症治疗，因此非常需要任何减少这种药物副作用的方法。我们建议开发此类化合物，应适用于多种恶性肿瘤。