EPI-7170

Here, we utilize all-atom molecular dynamics computer simulations to simulate covalent adducts of the small molecule ligands EPI-002 and EPI-7170 bound to the disordered androgen receptor transactivation domain...We compare the populations of protein-ligand interactions observed in covalent adduct ensembles to those observed in non-covalent ligand-bound ensembles and find substantial differences. Our results provide atomically detailed descriptions of covalent adducts formed by small molecules and an intrinsically disordered protein and suggest strategies for developing more potent covalent inhibitors of intrinsically disordered proteins.

We find that EPI-7170 binds androgen receptor more tightly than EPI-002 and we identify a network of intermolecular interactions that drives higher affinity binding. Our results suggest strategies for developing more potent androgen receptor inhibitors and general strategies for disordered protein drug design.

Androgen receptor (AR) has essential roles in the growth of prostate cancer and some breast cancers. Importantly, sequential combination treatments with palbociclib administered first then followed by EPI-7170, resulted in more cells accumulating in G1 and less cells in S phase than concomitant combination which was presumably because each inhibitor has a unique mechanism in modulating the cell cycle in cancer cells. Together these data support that the combination therapy was more effective than individual monotherapies to reduce tumor growth by targeting different phases of the cell cycle.