赖氨酸氧化酶家族在实体肿瘤基质靶向治疗中代表了一个有前途的目标，这是因为这个家族在交联和稳定成纤维胶原蛋白方面的重要性以及在肿瘤间质化中的已知作用。我们利用小分子药物设计方法，生成并验证了PXS-5505，这是一种首创的、高度选择性和强效的全谱赖氨酸氧化酶抑制剂。我们在体外和体内实验中证明，全谱赖氨酸氧化酶抑制剂可以减少化疗导致的胰腺肿瘤间质化和硬度，减少癌细胞的侵袭和转移，改善肿瘤灌注，增强自发的基因工程KPC模型中化疗的疗效，同时在人体源性胰腺癌移植模型中展示了抗纤维化作用。PXS-5505在组织中口服生物利用率好，安全有效地抑制赖氨酸氧化酶活性。我们的发现为发展一种全谱赖氨酸氧化酶抑制剂以降低基质，从而增强胰腺导管腺癌化疗的效果提供了合理性依据。© 2023. 作者。

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.© 2023. The Author(s).