Research progress in small-molecule modulators of protein-protein interactions

Protein-protein interactions (PPIs) are the fundamental unit of life activities and play a central role in almost every physiological and pathological process of all organisms. Dysregulation of PPIs underlies various diseases, including cancers, infectious diseases, immune diseases, and neurodegenerative diseases. From this perspective, PPIs are unambiguously regarded as attractive drug targets. Besides, the specificity of two proteins recognition warrants a more satisfactory binding selectivity for PPI-targeted drugs, which can help reduce disfavored off-target effects. Nevertheless, unlike other drug targets, the proteins of PPIs exhibit distinct properties, such as complex dynamics, unpredictable stabilities, wide and flat binding sites, and a lack of endogenous substrates. These differences lead to unavoidable challenges in developing PPI-targeted drugs, especially the small molecule PPI modulators (smPPIMs). Gratifyingly, although inevitable obstacles still exist, some smPPIMs have been successfully approved for marketing by the U.S. Food and Drug Administration (FDA) or are under different stages of clinical trials. To help researchers understand the opportunities and potentials of smPPIM, we would like to present a review to summarize the research progress of smPPIMs up to now. In this report, we divide this review into four parts. In the first part, we would like to discuss the four different modes of action of smPPIMs, including orthosteric stabilizers (or molecular glues), orthosteric inhibitors, allosteric stabilizers, and allosteric inhibitors. In the following part, we focus on typical development strategies that boost the discovery of smPPIMs, which we conclude as diversity library screening (DLS), fragment-based drug design (FBDD), peptidomimetic strategy, and computer-aided drug design (CADD). In the third part, we would like to shed light on three PPI targets we are interested in, which are PDE3A-SLFN12, CDK12-DDB1, and NTCP-HBV. Molecules that target these intriguing PPIs have great potential in curing cancer or blocking HBV infection but still lack sufficient attention. More detailed drug development including structure-activity relationship (SAR) study is also in great demand for these targets. We also select three popular PPI targets (NRF2-KEAP1, MDM2-p53, and PD1-PDL1) as challenging examples for discussion in detail. Besides the abovementioned PPIs, targets have been intensively investigated over the past decades, and SARs for compounds that target these PPIs have also been organized. Finally, in the last part, we present our perspectives regarding the therapeutic opportunity of PPIs and the future of smPPIMs discovery. We believe an interdisciplinary discovery paradigm, efficient constructions of a high-quality compound library, and the increasingly common usage of CADD technologies can promote the development of smPPIMs from random screening to rational design. Overall, this review provides our comprehensive view of PPI and smPPIM, thus inspiring further drug discovery in this field.