A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates—glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders.

药物开发的范式转变是发现利用泛素-蛋白酶体途径消除致病蛋白的小分子。在这里，我们提供了一种溶酶体中靶向蛋白质降解的方式。我们利用一种内源性溶酶体途径，其中蛋白质精氨酸甲基转移酶 （PRMT） 通过精氨酸甲基化启动底物降解。我们开发了一种异双功能小分子甲基精氨酸靶向嵌合体 （MrTAC），它将 PRMT1 募集到靶蛋白上以诱导溶酶体降解。MrTAC 化合物在不同细胞系、时间尺度和剂量下降解底物。MrTAC 降解需要靶蛋白甲基化，以便随后通过微自噬进行溶酶体递送。MrTAC 分子文库体现了 MrTAC 降解已知靶标和新底物（糖原合成酶激酶 3β、MYC、含溴结构域的蛋白 4 和组蛋白脱乙酰酶 6）的通用性。MrTAC 选择性降解靶蛋白，并在存活、转录和增殖中驱动生物功能丧失表型。总的来说，MrTAC 证明了内源性溶酶体蛋白水解在产生一类新型小分子降解剂中的效用。