MS023: Inspiration for the development of clinical candidates
Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Several years ago, the Icahn School of Medicine at Mount Sinai and the SGC collaborated to develop a type I PRMT selective chemical probe.
The resulting probe MS023 is highly potent against type I PRMTs and shows no inhibition towards type II/III PRMTs.
The core structural element of this probe can also be recognized in a clinical candidate in a Phase I study. Moreover, the crystal structures of both compounds show that they occupy the same binding pocket in a similar fashion (PDB codes 5E8R in PRMT6 and 6NT2 in PRMT1).
This probe story is an example of how studies of protein family members and the investigation of chemical probes for one member can cross-fertilize the exploration of other members of the same protein family and how chemical probes may contribute to the development of clinical candidates.
Figure. Left panel: Binding mode of MS023 in PRMT6 (PDB 5E8R). Right panel: MS023 is a potent Type 1 PRMT inhibitor.
For more information about the chemical probe MS023 visit the SGC website.
Chemical probe MS023 Negative control of MS023: MS094
The negative control (MS094) is available for purchase from Sigma.