Discovery of a first-in-class protein arginine methyltransferase 1 (PRMT1) degrader for nonenzymatic functions...

Among the type I Protein Arginine Methyltransferases (PRMTs), PRMT1 plays a predominant part in catalyzing asymmetric dimethylation of arginine residues on histone or nonhistone substrates. PRMT1 level is abnormally elevated in numerous cancer cell types and inflammation diseases. Compared to the enzymatic functions of PRMT1, its nonenzymatic functions are shortly investigated in diseases. Previous study has confirmed that the stability of orphan receptor TR3, a binding partner of PRMT1, is closely regulated by PRMT1, but the effect is independent of PRMT1's methyltransferase activity, but depends on the physical binding of PRMT1. To date, multiple inhibitors targeting methyltransferase enzymatic activity of PRMT1 are developed, but all of them lack selectivity for PRMT1. Among them, only GSK3368715 advanced to clinical trials but was discontinued in phase I due to inadequate efficacy and thrombosis toxicity. Currently, small molecule degraders are gaining significant attention due to their advantages in efficacy and selectivity in therapeutic applications. Presumably, a potent and selective PRMT1 degrader could serve as a valuable alternative in the treatment of PRMT1-driven diseases and act as an instrumental tool in uncovering additional nonenzymatic functions of PRMT1. To date, however, the development of a PRMT1 degrader remains a challenge, with no such agents reported. In this study, we present the design, synthesis and characterization of CM112 (compound 12), a first-in-class PRMT1 degrader, designed by tethering adamantane to MS023, a type I PRMTs pan inhibitor, via a 5-PEG linker. CM112 demonstrates a concentration- and time-dependent ability to induce PRMT1 degradation in various solid cancer cell lines. Additionally, CM112 shows high selectivity for PRMT1 degradation, without causing degradation of other type I PRMTs (PRMT3/4/6), although it retains potent inhibitory effects on their enzymatic activity. Pharmacokinetics studies indicated that CM112 possesses favorable bioavailability in mice. Notably, as anticipated, CM112 could target PRMT1's nonenzymatic function by downregulating the stability of the orphan receptor TR3, an effect not observed with the PRMT1 inhibitor MS023, that is in consistence with the previous findings. Taken together, CM112 represents a valuable tool for elucidating the unknown, methyltransferase-independent roles of PRMT1 in disease progression and pave the way for developing more potent and drug like PRMT1 degraders in future.