When expressed in its wild-type form (~50% of human tumors), the function of the tumour-supressor protein p53 can be inhibited by the Murine Double Minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of p53 represents an attractive strategy against several types of cancers.
In this study, we have used Ultrafast Shape Recognition (USR) to screen the set of FDA-approved drugs for novel p53-MDM2 inhibitors using a potent binder of the p53-pocket on MDM2 of as template. Subsequent molecular modelling supported the potential role of the resulting USR hits as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner.
Telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers.
From a methodological perspective, this study demonstrates that the adopted USR-based virtual screening protocol is useful for identifying molecules with whole-cell anti-cancer activity as well as potential small molecule protein-protein interaction inhibitors.This is the fourth publication reporting a successful prospective application of USR (the others are here, here and here), with some more applications being currently prepared for publications.
The paper is available here.