Selective inhibitors to improve CPT-11 therapy

描述（由申请人提供）：CPT-11是一种高效的基于喜树碱的抗癌药物，目前已获批用于治疗结肠癌。该化合物是一种前体药物，可被羧酸酯酶激活，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在小肠中高度表达的人肠羧酸酯酶（CE）直接激活胆汁中分泌的CPT-11所致。我们假设，通过抑制这种酶，减少SN-38将在肠道中由药物水解产生，从而降低与CPT-11治疗相关的毒性。因此，本申请的目的是开发可用于改善与CPT-11给药相关的毒性的选择性CE抑制剂。基于原型化合物苯偶酰的高效、无毒小分子抑制剂已经被鉴定，并且我们建议开发这些试剂用于抑制人肠道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物化学和生物学性质;和4）在hiCE在小鼠肠中表达的血浆酯酶缺陷小鼠模型中评估它们调节CPT-11诱导的毒性的功效。我们相信，如果成功，这些研究将提供可以改善CPT-11给药相关的迟发性腹泻的试剂，并可能允许药物的剂量强化。这可能会导致抗肿瘤疗效的改善，此外，还可能允许使用CPT-11治疗对该药物表现出边际应答的耐药性更强的恶性肿瘤。 公共卫生相关性：这些研究将确定和表征可以降低CPT-11治疗相关毒性的新药。由于这种化学治疗剂广泛用于癌症治疗，因此任何减少这种药物副作用的方法都是非常可取的。我们建议开发这样的化合物，应具有适用性的各种恶性肿瘤。

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.