Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Nat Commun. 2024 Oct 8;15(1):8695. doi: 10.1038/s41467-024-52685-9.
Targeted protein degradation has emerged as a novel therapeutic modality to treat human diseases by utilizing the cell's own disposal systems to remove protein target. Significant clinical benefits have been observed for degrading many intracellular proteins. Recently, the degradation of extracellular proteins in the lysosome has been developed. However, there have been limited successes in selectively degrading protein targets in disease-relevant cells or tissues, which would greatly enhance the development of precision medicine. Additionally, most degraders are not readily available due to their complexity. We report a class of easily accessible Folate Receptor TArgeting Chimeras (FRTACs) to recruit the folate receptor, primarily expressed on malignant cells, to degrade extracellular soluble and membrane cancer-related proteins in vitro and in vivo. Our results indicate that FRTAC is a general platform for developing more precise and effective chemical probes and therapeutics for the study and treatment of cancers.
靶向蛋白降解技术已成为一种新型的治疗方法，可以利用细胞自身的处理系统来清除靶蛋白，从而治疗人类疾病。在降解许多细胞内蛋白方面已经观察到了显著的临床益处。最近，溶酶体中外源蛋白的降解已经被开发出来。然而，在疾病相关细胞或组织中选择性降解靶蛋白的成功率有限，这将极大地促进精准医学的发展。此外，由于其复杂性，大多数降解剂不易获得。我们报告了一类易于获得的叶酸受体靶向嵌合体（FRTACs），可以招募主要在恶性细胞上表达的叶酸受体，在体外和体内降解细胞外可溶性和膜相关的癌症相关蛋白。我们的结果表明，FRTAC 是开发更精确和有效的化学探针和治疗癌症的研究和治疗的通用平台。
