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

大约90%的胰腺导管腺癌（PDAC）患者将在5年内死于该疾病。开发新的靶向治疗对于提高患者的生存率至关重要。成纤维细胞激活蛋白（FAP）是一种II型整体膜蛋白酶，在90%以上的上皮肿瘤基质中大量选择性表达，包括PDAC。在TargPanc中，我们提出创建一种高度选择性的fap靶向小分子化疗药物，这将改善胰腺癌肿瘤的药物传递，同时限制脱靶效应并最大化疗效。高亲和力FAP配体已被报道。我们计划将一种新的β -葡糖苷- phb - β -拉帕酮前药与我们设计的单价和多价- FAP配体结合。这种新型的fap靶向前药通过β -葡萄糖醛酸酶在最佳pH的坏死肿瘤微环境中释放β -lapachone，以及靶向PDAC细胞中过表达的NAD(P)H脱氢酶醌1 （NQO1）和5-脂氧合酶（5-LO）酶的β -lapachone毒素，实现多层特异性。我们将首先合成、优化和测试这种小分子偶联物的各种衍生物，以获得最佳的稳定性和药物释放。然后，我们将在体外PDAC细胞系和体内PDAC特异性KPC基因工程小鼠模型中测试该结合物。这种结合物的癌细胞特异性也将使这种前药有效地治疗其他预后不良的实体肿瘤。我们假设，与现有疗法相比，这种更小的靶向化疗将具有更大的肿瘤穿透性和改善的药代动力学分布，并且具有有限的全身毒性，最终延长患者的总体生存期。

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.