Selection and preclinical development of a bacteria-targeting, non-antibiotic lead candidate to improve cancer chemotherapy outcomes

该项目的长期目标是预防化疗引起的腹泻（CID）的治疗辅助手段 基于一种针对肠道细菌的全新作用机制。此快速通道SBIR提案 概述了在研究性新药中选择待评价的主要开发候选药物的策略 （IND）-使研究能够支持首次人体试验。该项目的重点是预防腹泻 与伊立替康（IRI）相关，IRI是一种用于治疗晚期结直肠癌和胰腺癌的重要药物 患者强烈的、迟发性腹泻是减少、推迟或停止IRI化疗的主要原因。 IRI的抗癌活性剂是SN 38，一种有效的拓扑异构酶I抑制剂。作为消除的一部分， 在体内，SN 38主要由肝脏解毒为无活性的葡萄糖醛酸苷（SN 38-G）， 穿梭于下胃肠道β-葡萄糖醛酸苷酶（GUS）在肠上皮细胞亚群中表达， 细菌将SN 38-G代谢回SN 38，SN 38对肠细胞具有高毒性。这种SN 38的重新激活， 肠道微生物组中的细菌GUS是最终导致严重的延迟性腹泻的关键触发事件。 一种选择性的、非专利的细菌GUS抑制剂（SBX-1）先前被证明可以减轻IRI诱导的细胞凋亡。 啮齿类动物腹泻该项目的第1阶段公开了SBX-1的五种专有类似物，并概述了 有效性/耐受性研究，以选择两种最有前途的类似物进入II期 SBIR研究。主要候选人将在第二阶段的第一个目标中选出。第二阶段剩余活动 包括化学/制造/控制（CMC）相关工作和监管/安全性临床前研究， 将该项目从药物发现过渡到临床前开发。 目的1（第1阶段）：在体外分析新型SBX-1类似物的脱靶药理学、细胞毒性， 代谢的稳定性。目标2（阶段1）：确定两个最有前途的SBX-1类似物 基于它们的治疗窗口和正式临床前研究的候选资格。目标3（第2阶段）：选择电极导线 候选人生成CMC和其他非GLP临床前数据，以支持与FDA的IND前会议。 目标4（第2阶段）：开展与CMC相关的活动，以便能够对拟定的先导产品进行正式评价 GLP毒理学和安全药理学研究的候选人。拟议的第2阶段工作中的一项关键交付成果 是一个临床前数据包，将充分资格的主要候选人进一步评价在急性给药， 在接受化疗的晚期结直肠癌和/或胰腺癌患者中进行的首次人体临床试验 含伊立替康的化疗。

The long-term objective of this project is a therapeutic adjunct to prevent chemotherapy-induced diarrhea (CID) based on a completely new mechanism of action targeting enteric bacteria. This Fast-Track SBIR proposal outlines the strategy for selecting a lead development candidate to be evaluated in investigational new drug (IND)-enabling studies to support a first-in-human trial. The focus of this project is prevention of diarrhea associated with irinotecan (IRI), an important drug used to treat advanced colorectal and pancreatic cancer patients. Intense, delayed diarrhea is the major reason for reducing, postponing or stopping IRI chemotherapy. The cancer-killing, active agent of IRI is SN38, a potent topoisomerase I inhibitor. As part of its elimination from the body, SN38 is detoxified primarily by the liver to an inactive glucuronide (SN38-G) that is subsequently shuttled to the lower gastrointestinal tract. The β-glucuronidase enzyme (GUS) expressed in a subset of gut bacteria metabolizes SN38-G back into SN38, which is highly toxic to enterocytes. This reactivation of SN38 by bacterial GUS in the gut microbiome is a key triggering event leading ultimately to serious, delayed diarrhea. A selective, non-proprietary bacterial GUS inhibitor (SBX-1) was previously shown to alleviate IRI-induced diarrhea in rodents. Phase 1 of this project discloses five proprietary analogs of SBX-1 and outlines the efficacy/tolerability studies to enable selection of the two most promising analogs to advance into Phase 2 SBIR studies. The lead candidate will be selected in the first aim of Phase 2. The remaining Phase 2 activities include chemistry/manufacturing/control (CMC)-related work and regulatory/safety preclinical studies that will transition this project from drug discovery to preclinical development. Aim 1 (Phase 1): Profile novel SBX-1 analogs in vitro for their off-target pharmacology, cytotoxicity, metabolism liability and stability in plasma. Aim 2 (Phase 1): Identify the two most promising SBX-1 analogs based on their therapeutic window and candidacy for formal preclinical studies. Aim 3 (Phase 2): Select lead candidate. Generate CMC and additional non-GLP preclinical data to support a pre-IND meeting with the FDA. Aim 4 (Phase 2): Conduct CMC-related activities to enable formal evaluations of the formulated lead candidate in GLP toxicology and safety pharmacology studies. A key deliverable in the proposed Phase 2 work is a preclinical data package that will adequately qualify the lead candidate for further evaluation in an acute-administration, first-in-human clinical trial in advanced colorectal and/or pancreatic cancer patients undergoing irinotecan-containing chemotherapy.