A New Class: Protein-Protein Interactions As Drug Targets

By Anjani Shah

November 3, 2017 | Since the onset of targeted drug discovery, a little before the turn of the millennium, intracellular drug targets have primarily been enzymes—proteins such as kinases—that catalyze reactions. Such enzymatic targets are easier to develop drugs against mainly because enzymes are easy to screen against in biochemical assays that can be easily adapted to high-throughput screening formats. And because enzyme targets have evolved to bind small molecules (such as ATP in the case of kinases) so there are already small pockets, or grooves, in the target enzyme that synthetic small molecules with drug potential can be developed against.

However, a new type of intracellular drug target—Protein-Protein Interactions (PPIs)—are now expanding the space in which to search for new types of medicines. PPIs are protein complexes inside the cell that play regulatory or structural roles. Examples of PPI targets include:

• Protein chaperones bound to other proteins to help them fold correctly,
• Signaling complexes such as those involved in apoptosis (programmed cell death)
• Proteins bound to other proteins to aid the ubiquitination process that marks the target protein for degradation
• Complexes of proteins bound to each other or to DNA to regulate transcription or to direct epigenetic markings such as acetylation or methylation on DNA.

Biology and disease is more complex than just over-active or under-active enzymes; many diseases are caused by protein complexes not working properly. Targeting PPIs can lead to completely new drugs: disrupters and stabilizers rather than enzymatic inhibitors or activators. PPIs used to be considered “undruggable” targets because of their larger, flatter surfaces as compared to enzymes, but new technologies are changing that.

Biophysical techniques such as nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR), which are employed for, among other things, detecting the interaction of molecules with one another in PPI complexes, have become more robust. These technologies are now adaptable to screening applications where large numbers of compounds need to be analyzed reproducibly and in a short amount of time—not high throughput speeds yet, but fast enough to screen smaller, more-focused compound libraries.  

Advances in NMR and X-ray crystallography have also enabled more success in structure-based drug design (SBDD) methods. Improved SBDD methods aid the tricky task of designing small molecule compounds that will still interact with the larger, flatter surfaces of PPI sites. The first (medium-sized) small molecule against a PPI target was launched in 2016 to treat CLL, a type of leukemia. The drug, called Venetoclax, inhibits the protein BCL2 which is part of an “anti-apoptosis” complex.

New drug design techniques are also broadening the types of molecules that researchers are exploring for accessing PPI sites—the small molecules are getting slightly bigger. Peptide macrocyclization and constraining tricks are being developed with the goal of enabling “middle-sized molecules” to penetrate cells and be developed into oral drugs. The hope is that these new types of synthetic peptides will be able to be delivered as oral medications for targeting intracellular PPIs; a few are close to reaching the market.

The turn of the millennium brought a boom of big molecules, namely biologics, as the basis of new drugs. However, biologics are limited to cell-surface targets. The next decade or two may host a resurgence in small and middle-size molecule drug development. The hope is that this expanded chemical space of potential drug entities will allow access to the new class of intracellular PPI targets, which has the promise of bringing new types of medicines for difficult-to-treat diseases. Small is beautiful too.