An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor

Protein
arginine methyltransferases (PRMTs) represent promising
drug targets. However, the lack of isoform-selective chemical probes
poses a significant hurdle in deciphering their biological roles.
To address this issue, we devised a library of 100 diverse adenosine
analogues, enabling a detailed exploration of the active site of PRMTs.
Despite their close homology, our analysis unveiled specific chemical
trends unique to the individual members. Notably, compound YD1130
demonstrated over 1000-fold selectivity for PRMT4 (IC50 < 0.5 nM) over a panel of 38 methyltransferases, including the
other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular
substrate methylation, breast cancer cell colony formation, and tumor
growth in the animal model, surpassing or matching known PRMT4-specific
inhibitors. In summary, our focused library not only illuminates the
intricate active sites of PRMTs to facilitate the discovery of highly
potent and isoform-selective probes but also offers a versatile blueprint
for identifying chemical probes for other methyltransferases.