Epigenetic events include DNA methylation, histone modifications, chromatin remodeling, and the influence of noncoding RNAs [1], [2]. Epigenetic dysregulation is a common feature of most cancers, typically occurring directly by altering the epigenetic machinery [3]. Over the last several years, new generation selective epigenetic drugs targeting mutated or translocated proteins in cancer have entered clinical development. Histone methylation inhibitors (EZH2i), histone deacetylation inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been approved by the FDA and the EMA [4], [5]. Arginine methylation is a common post-translational modification that serves as an epigenetic regulatory factor for transcription, playing a crucial role in DNA damage signaling, precursor messenger RNA splicing, cellular signaling, and messenger RNA translation [6], [7]. The PRMTs family members are key enzymes involved in the process of arginine methylation of proteins, and nine PRMTs members have been identified in mammalian cells. PRMTs can be divided into three categories: type I, II and III by regulating different forms of arginine methylation [8].

PRMT6 is a member of the type I PRMTs family, and is the most important protein that methylates Arg2 (H3R2) of histone H3 [9], [10], which is involved in the episodic regulation of gene expression [11], [12], [13], DNA repair [14], alternative splicing [15], [16], cell proliferation and senescence [17], [18], [19], [20], [21], [22], and DNA methylation [23]. In addition, PRMT6 can methylate non-histone substrates such as CRAF, PTEN, BAG5, p21, and GPS2 [24], [25], [26], [27], [28]. In addition to its repressive epigenetic role, PRMT6 can also serve as a co-activator of steroid hormone receptors, which requires the methyltransferase activity of PRMT6. The transcription factor NF-κB interacts with PRMT6 and acts as a co-activator to promote NF-κB expression of target genes [29]. The transcription factor LEF1 activates cyclin D1 expression by recruiting PRMT6 to the promoter of cyclin D1 [30].

Fig. 1 shows representative PRMT6 inhibitors that have been reported. Type I PRMTs have a S-adenosylmethionine (SAM) pocket and a substrate pocket in close proximity [31], [32]. The first PRMT6 covalent inhibitor MS117 was obtained by derivatization of the structure of MS023 [33]. GSK3368715 was a pan inhibitor of type I PRMTs, which had inhibitory activity against PRMT1, 3, 4, 6, and 8 [32]. GMS was a pan inhibitor of PRMTs family reported in 2016, and its IC50 value for PRMT6 was 90 nM [34]. MS049 was a dual inhibitor that targets PRMT4 and PRMT6, with high efficiency, selectivity and cellular activity. Its inhibitory effects were not limited to PRMT4 and PRMT6, and might also affect other members of the PRMTs family, such as PRMT8 [35]. EPZ020411 was reported in 2015 as the first potent selective PRMT6 inhibitor with the IC50 value of 10 nM [36]. The first PRMT6 allosteric inhibitor SGC6870 was reported in 2021. SGC6870 showed excellent selectivity, but its antitumor activity has not been reported [37]. Cpd. a25 was a PRMT6 selective inhibitor reported in 2023 by us and collaborators, with more than 25-fold selectivity for PRMT1/8 and more than 50-fold selectivity for PRMT3/4/5/7 [38].

The existing PRMTs inhibitors can only inhibit canonical biological function-methylation, and have no inhibitory effect on some non-canonical biological functions; for example, they function in conjunction with some transcription factors [30]. PROTAC (protein targeting chimeras) is a drug development technology that uses the ubiquitin proteasome system (UPS) to degrade target proteins, and hydrophobic tagging (HyT) also is a successful technical strategy for the selective degradation of target proteins [39], [40]. The HyT-based degrader contains a large hydrophobic moiety which is connected to the ligand of the target protein through a linker [41]. The hydrophobic moiety, which attaches to the protein surface, mimics the denatured state of the target protein, resulting in proteasome system-mediated degradation of the target protein [39], [42], [43]. To date, no selective degraders of PRMT6 have been reported. Here, we reported the discovery of a PRMT6 selective degrader, which was designed by connecting an intermediate of a PRMT6 inhibitor to an adamantane moiety.