Modulation of Protein-Protein Interactions for the Development of Novel Therapeutics

Abstract

Protein-protein interactions (PPIs) underlie most biological processes. An increasing interest to investigate the unexplored potential of PPIs in drug discovery is driven by the need to find novel therapeutic targets for a whole range of diseases with a high unmet medical need. To date, PPI inhibition with small molecules is the mechanism that has most often been explored, resulting in significant progress towards drug development. However, also PPI stabilization is gradually gaining ground. In this review, we provide a focused overview of a number of PPIs that control critical regulatory pathways and constitute targets for the design of novel therapeutics. We discuss PPI-modulating small molecules that are already pursued in clinical trials. In addition, we review a number of PPIs that are still under preclinical investigation but for which preliminary data support their use as therapeutic targets.

Figure 1

The “hot spot” concept and the rationale for designing PPI modulators. Upper panel: an orthosteric small molecule inhibitor binds to the interaction interface of two proteins, thereby preventing their interaction. An allosteric inhibitor binds to the interacting protein A outside of the PPI surface, inducing a conformational change that inhibits its association with protein B. Lower panel: similarly, an orthosteric small molecule stabilizer binds to the PPI surface and stabilizes the interaction between proteins B and C, whereas an allosteric stabilizer changes the conformation of protein C so that protein D can bind with higher affinity. PPI, protein–protein interaction.

Figure 2

Small molecule inhibitors in clinical and preclinical stage interfere with PPIs involved in the apoptosis pathway as an anticancer treatment. This scheme illustrates three clinically important PPIs: 1) MDM2/p53; 2) Bcl2, Bcl-XL/Bak, Bax; and 3) IAP/caspases, and their role in the apoptosis cascade. In blue, proteins are depicted that are targeted for inhibition by small molecules and in pink their interaction partners that promote apoptosis. The panels below depict the chemical structures of representative small molecule inhibitors that interfere with the respective PPIs. IAP, inhibitor of apoptosis protein; MDM2, murine double minute 2; PPI, protein–protein interaction.

Figure 3

Modulation of liganded receptors with small molecules. (a) PPI inhibitors of liganded receptors. Small molecules designed to inhibit cytokine signaling of IL-17 and IL-2 through their respective receptors IL-17R and IL-2R. The GR/Hsp90 inhibition by silibinin is involved in Cushing's syndrome and the interaction of ICAM1 with LFA-1 is targeted by lifitegrast to obtain immunosuppression. (b) Beneficial effects of stabilization of 14-3-3 protein interaction with GR or ER. The chemical structures of the depicted molecules are provided except for the structure of Ensemblins, which is not publicly available. ER, estrogen receptor; GR, glucocorticoid receptor; IL, interleukin; PPI, protein–protein interaction.

Figure 4

PPI stabilizers in cancer treatment and in the modulation of immunosuppression. (a) Paclitaxel is a representative allosteric PPI stabilizer that preserves tubulin formation. (b) FK506 and rapamycin are potent immunosuppressants acting as direct stabilizers of protein interactions with FKBP12. PPI, protein–protein interaction.