Protein-Protein Interactions and Cancer

p53-bound
Rendering of p53 Tumor Suppressor Bound to DNA. Image courtesy the Protein Data Bank/Research Collaboratory for Structural Bioinformatics.

Protein-protein interactions (PPI) are key regulatory processes in cancer because many proteins that directly interact with binding partners regulate tumor growth. Recognizing this role of PPIs, they have been the focus of recent drug development/discovery efforts. In the recent CHI Drug Discovery Chemistry conference, an entire session of the Protein-Protein Interaction meeting was dedicated to targeting PPI for cancer.

Kurt Deshayes, PhD from Genentech talked about targeting cancer by disrupting PPIs. Of all the hallmarks of cancer described by Hanahan and Weinberg, Deshayes? targeting focused on the hallmark ?evading apoptosis?. Inhibitors of apoptosis (IAP) are a group of proteins that, as the name suggests, inhibit apoptosis. IAP proteins are overexpressed in cancer and represent promising anti-cancer targets. A bivalent IAP antagonist, BV6 was developed as a potent cell death inducer (14 nM IC50). Another small molecule antagonist of IAP, GDC-0152 is being tested and has similar or higher potency against cancer cells.

In addition to IAP, Bcl2- family proteins have been shown to regulate apoptosis. There is a strong correlation between Bcl family member protein expression, tumor growth and resistance to therapy. Consequently, these proteins (binding each other via PPI) have been recently targeted for drug discovery. For example, the BH3 mimetic small molecule, ABT-737 can bind the BIM groove within Bcl-XL and inhibit Bcl2 proteins. In addition, another compound ABT-199 is an effective inhibitor and has been found to have efficacy against primary patient-derived leukemia cells and also clinically in patients.

P53 is a tumor suppressor and it controls pathways that prevent malignant transformation. However, p53 is mutated in >50% of all human cancers and represents a good target for cancer therapy. Daqing Sun from Amgen talked about the discovery of AMG 232, a small molecule inhibitor of the MDM2-p53 interaction. Initial high-throughput screens were used to identify MDM2-p53 inhibitors, which led to the eventual development of AMG 232 that is more potent than most p53 inhibitors currently in clinical development. This compound is being tested in the clinic and may prove to be effective against different cancer types.

Roderick Hubbard from the University of York is currently involved in drug discovery using a fragment-based approach to target PPI. He asserts that fragment-based drug discovery (FBDD) represents ?a powerful tool for discovering drug leads?. At this meeting, he mentioned about his work that focused on targeting MDM2-p53 pathway and beta-catenin signaling for cancer. Both these targets yielded success in the form of lead compounds that are being tested for further development. Recently, his team has been working on Bcl2 family proteins, also important in cancer signaling. These various PPIs are highly significant in cancer biology and targeting them for drug discovery using novel approaches like FBDD may yield success.

In spite of the challenges involved, small molecules that interfere with PPIs have been found by different drug discovery methods. Based on the testimony of various scientists from academia and the industry at the Drug Discovery Chemistry meeting, it is obvious that targeting PPIs is ?hard work but potentially very fruitful?.

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