Selective inhibitors to improve CPT-11 therapy

描述（由申请人提供）：CPT-11是一种高效的喜树碱类抗癌药物，目前已被批准用于治疗结肠癌。这种化合物是一种前药，被羧酸酯酶激活产生SN-38，一种有效的拓扑异构酶I毒药。CPT-11的剂量限制性毒性是在给药后48-96小时发生迟发性腹泻。这被认为部分是由于胆汁中分泌的CPT-11被小肠中高度表达的人类肠道羧酸酯酶（CE）直接激活所致。我们推测，通过抑制这种酶，肠道内的药物水解会产生减少的SN-38，从而降低CPT-11治疗相关的毒性。因此，该应用的目标是开发选择性CE抑制剂，可用于改善CPT-11给药相关的毒性。以苯并为基础的高效、无毒的小分子抑制剂已经被发现，我们建议开发这些药物用于抑制人类肠道CE （hiCE）。将采用核磁共振、x射线晶体学、药物化学、QSAR、生化和体内方法来验证合适化合物的有效性。该应用的具体目的是：1)确定苯甲醚抑制CE的机制；2)开发苯的水溶性类似物；3)评价这些化合物的生化和生物学特性；4)在小鼠肠道中表达hiCE的血浆酯酶缺陷小鼠模型中，评估它们在调节cpt -11诱导的毒性方面的功效。我们相信，如果成功，这些研究将提供试剂，可以改善与CPT-11给药相关的延迟性腹泻，并可能允许药物剂量强化。这可能会提高抗肿瘤疗效，而且，也可能允许使用这种CPT-11来治疗对这种药物表现出边际反应的更耐药的恶性肿瘤。

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.