Protein-Protein Interactions (PPIs) that are part of the costimulatory and coinhibitory (immune
checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets
for immunomodulation. Biologics targeting them have already achieved considerable clinical success
in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and
belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab,
and avelumab). In view of such progress, there have been only relatively limited efforts toward developing
small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because
they, as all other PPIs, are difficult to target by small molecules and were not considered druggable.
Nevertheless, substantial progress has been achieved during the last decade. SMPPIIs proving the feasibility
of such approaches have been identified through various strategies for a number of cosignaling
interactions including CD40-CD40L, OX40-OX40L, BAFFR-BAFF, CD80-CD28, and PD-1-PD-L1s.
Here, after an overview of the general aspects and challenges of SMPPII-focused drug discovery, we
review them briefly together with relevant structural, immune-signaling, physicochemical, and medicinal
chemistry aspects. While so far only a few of these SMPPIIs have shown activity in animal models
(DRI-C21045 for CD40-D40L, KR33426 for BAFFR-BAFF) or reached clinical development (RhuDex
for CD80-CD28, CA-170 for PD-1-PD-L1), there is proof-of-principle evidence for the feasibility of
such approaches in immunomodulation. They can result in products that are easier to develop/
manufacture and are less likely to be immunogenic or encounter postmarket safety events than
corresponding biologics, and, contrary to them, can even become orally bioavailable.