RESCUING DESTABILIZED MUTANT TUMOR SUPPRESSORS USING SMALL MOLECULES

Decades of research efforts, expedited in recent years by next-generation sequencing technologies, have carefully cataloged recurrent driver gene mutations in many different cancers. A somewhat dismaying insight from these studies is the observation that the underlying genetic alterations in cancer are dominated by tumor suppressors rather than oncogenes: most cancers contain alterations in 3-5 tumor suppressor genes, and at most 1 oncogene. This is problematic because extant drug discovery expertise is firmly centered around inhibitors of enzyme activity, and kinases especially: this leaves our community collectively ill-equipped to tackle the challenge of designing compounds that restore the function of deactivated tumor suppressors.

The Karanicolas Lab been developing computational tools specifically catered to the shallow surface pockets typical of sites that are not naturally evolved for small-molecule binding. By exploring low-energy fluctuations of the protein surface, we can reveal cryptic druggable pockets - and then use these as the basis for structure-based virtual screening.

We recently used these tools to identify a novel druggable sites on the surface of tumor suppressors p53 and VHL. On the basis of the pockets observed in our simulations, we then developed a series of compounds that restore activity to destabilized mutant p53, and a series of compounds that restore activity to destabilized mutant VHL.

Moving forward, we now seek to identify cancer-driving destabilizing mutations in other tumor suppressors, and then use our unique computational approach to develop compounds that will restore their activity. We anticipate that the compounds developed over the course of our studies can be used to explore the potential therapeutic utility of restoring tumor suppressive activity, and may also serve as a starting point for new classes of cancer therapeutics.