A Conditionally Activable Small Molecule Pro-Drug Conjugate for Targeted Treatment of Pancreatic Cancer

用于胰腺癌靶向治疗的条件激活小分子前药偶联物

• 批准号: EP/Y036336/1
• 负责人: Gonçalo Bernardes
• 金额: $ 16.19万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY036336%2F1
• 关键词: Conditionally; Activable; Small; Molecule; Pro

Approximately 90% of patients suffering from pancreatic ductal adenocarcinoma (PDAC) will die from the disease within five years. Development of novel targeted therapies is essential to improve patient survival. Fibroblast activating protein (FAP) is a type II integral membrane protease that is abundantly and selectively expressed in the stroma of more than 90% of epithelial tumours, including PDAC. In TargPanc, we propose the creation of a highly selective FAP-targeted small molecule chemotherapeutic which would improve drug delivery to pancreatic cancer tumours while also limiting off-target effects and maximizing efficacy. High-affinity FAP ligands have been reported. We plan to conjugate a novel beta-glucuronide-PHB-beta-lapachone prodrug to mono and multivalent- FAP ligands we have designed. This novel FAP-targeted prodrug achieves multi-layer specificity through the beta-glucuronidase dependent release of the warhead (beta-lapachone) in a necrotic tumour microenvironment of optimal pH, as well as the beta-lapachone toxin targeting the overexpressed NAD(P)H dehydrogenase quinone 1 (NQO1) and 5-lipoxygenase (5-LO) enzymes in PDAC cells. We will first synthesize, optimize, and test various derivatives of this small molecule conjugate for optimal stability and drug release. We will then test the conjugate in vitro in PDAC cell lines and in vivo in PDAC-specific KPC genetically engineered mouse models. The cancer cell specificity of this conjugate will also allow this prodrug to effectively treat other solid tumours with poor prognoses. We hypothesize that this smaller, target-specific chemotherapeutic will have greater tumour penetration and improved pharmacokinetic distribution with limited systemic toxicity compared to existing therapies, ultimately extending overall patient survival.

大约90％的患有胰腺导管腺癌（PDAC）的患者将在五年内死于该疾病。新型靶向疗法的发展对于改善患者生存至关重要。成纤维细胞激活蛋白（FAP）是II型积分膜蛋白酶，在超过90％的上皮肿瘤（包括PDAC）的基质中大量和选择性地表达。在Tar​​gpanc中，我们提出了高度选择性FAP靶向的小分子化学治疗剂的创建，该化疗将改善药物向胰腺癌肿瘤的递送，同时还限制了脱靶效应并最大程度地提高功效。已经报道了高亲和力FAP配体。我们计划结合一种新型的β-葡萄糖醛酸甘蓝 - β-beta-lapachone前药到我们设计的单声道和多价 - FAP配体。这种新颖的FAP靶向前药通过在最佳pH的坏死肿瘤微环境中的β-葡萄糖酶依赖性释放（β-拉帕酮）来实现多层特异性，以及靶向过表达的NAD（P）HAD（p）HASASE dehydrogen Quinse Quinnose Quinone Quinone Quinone 1（NQ）1（beta-lapachone toxin） PDAC细胞中的（5-lo）酶。我们将首先合成，优化和测试该小分子结合物的各种衍生物，以获得最佳稳定性和药物释放。然后，我们将在PDAC细胞系中的体外和PDAC特异性KPC基因工程小鼠模型中的体外测试。该结合物的癌细胞特异性还将使该前药有效治疗其他预后的其他实体瘤。我们假设，与现有疗法相比，这种较小的，特异性的化学治疗性将具有更大的肿瘤渗透和改善的药代动力学分布，系统性毒性有限，最终延长了总体患者的生存。