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)的辅助治疗。 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 概述了在研究新药中选择要评估的领先开发候选者的策略 (IND)-使研究能够支持第一次人体试验。这个项目的重点是预防腹泻。 与伊立替康(IRI)有关，IRI是用于治疗晚期结直肠癌和胰腺癌的重要药物 病人。剧烈的延迟性腹泻是减少、推迟或停止IRI化疗的主要原因。 IRI的杀癌活性物质是一种强有力的拓扑异构酶I抑制剂SN38。作为其消除的一部分 体内的SN38主要由肝脏解毒为一种不活跃的葡萄糖醛酸苷(SN38-G)，随后 穿梭到下胃肠道。β-葡萄糖醛酸苷酶(GUS)在肠道中的表达 细菌将SN38-G代谢回SN38，SN38对肠道细胞有很强的毒性。通过以下方式重新激活SN38 肠道微生物群中的细菌GUS是一个关键的触发事件，最终导致严重的迟发性腹泻。 一种选择性的、非专利的细菌GUS抑制剂(SBX-1)先前被证明可以缓解IRI诱导的 啮齿动物的腹泻。该项目的第一阶段公开了SBX-1的五种专有类似物，并概述了 有效性/耐受性研究，使两种最有希望的类似物能够进入第二阶段 SBIR研究。首席候选人将在阶段2的第一个目标中选出。 包括与化学/制造/控制(CMC)相关工作和监管/安全临床前研究 将这一项目从药物发现过渡到临床前开发。 目的1(阶段1)：体外对新型SBX-1类似物进行非靶标药理、细胞毒性、 血浆中的代谢易感性和稳定性。目标2(阶段1)：确定两个最有希望的SBX-1类似物 根据他们的治疗窗口和正式临床前研究的候选情况。目标3(阶段2)：选择销售线索 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(阶段2)：开展与CMC相关的活动，以便能够对制定的Lead进行正式评估 GLP毒理学和安全性药理学研究的候选人。提议的第二阶段工作中的关键交付成果 是一个临床前数据包，将充分地使主要候选人有资格在急性管理中进行进一步评估， 对晚期结直肠癌和/或胰腺癌患者进行的首例人类临床试验 含有伊立替康的化疗。

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.