Abstract：
Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. The incidence of the latter two events may be associated with inhibition-driven pharmacology as a high and sustained concentration of inhibitor is required for therapeutic effect. The degradation of PRMT1 using a proteolysis targeting chimera (PROTAC) may be superior to inhibition as proceeds via event-driven pharmacology where a PROTAC acts catalytically at a low dose. PROTACs containing the same pharmacophore as GSK3368715, combined with a motif that recruits the VHL or CRBN E3-ligase, were synthesised. Suitable cell permeability and target engagement were shown for selected candidates by the detection of downstream effects of PRMT1 inhibition and by a NanoBRET assay for E3-ligase binding, however the candidates did not induce PRMT1 degradation. This paper is the first reported investigation of PRMT1 for targeted protein degradation and provides hypotheses and insights to assist the design of PROTACs for PRMT1 and other novel target proteins.
摘要：
靶向蛋白质精氨酸甲基转移酶1（PRMT1）已成为癌症治疗中一种有前途的治疗策略。第一个进入临床的PRMT1抑制剂GSK3368715的1期临床试验，由于缺乏临床疗效而提前终止，广泛的治疗紧急效果，和剂量限制性毒性。后两种事件的发生率可能与抑制驱动的药理学有关，因为治疗效果需要高浓度和持续的抑制剂。使用蛋白水解靶向嵌合体(PROTAC)的PRMT1的降解可能优于通过事件驱动的药理学进行的抑制,其中PROTAC在低剂量下催化起作用。含有与GSK3368715相同药效团的PROTACs，结合了一个招募VHL或CRBNE3连接酶的基序，是合成的。通过检测PRMT1抑制的下游效应和通过NanoBRET对E3连接酶结合的测定，显示了选定候选物的合适细胞通透性和靶标接合，然而,候选物没有诱导PRMT1降解.本文是对PRMT1靶向蛋白质降解的首次报道研究，并提供了假说和见解，以帮助设计PRMT1和其他新型靶蛋白的PROTACs。
