Toward Small-Molecule Inhibition of Protein–Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions

Abstract

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.

Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction

“…They could offer useful alternatives to biologics such as antibodies especially given that small molecules are less likely to be immunogenic and have the potential of being orally bioavailable. Considerable progress along these lines has been made in the last decade even though only a few costimulatory PPI-targeting small molecules have reached preclinical (animal model) stages so far (e.g., our compounds, including the present ones, for CD40–CD154 and KR33426 for BAFFR–BAFF) and even fewer have reached clinical development (RhuDex for CD80–CD28 and CA-170 for PD-1–PD-L1) [ 47 , 50 ]. As a direct follow-up on our work to identify drug-like small-molecule inhibitors of the CD40–CD154 costimulatory PPI [ 56 ], here, we report a second set of molecules designed to explore the effect of different substituents and substituent positions (e.g., 7 – 9 ), different linkers (e.g., 16 – 19 ), longer ring chains ( 14 , 15 ), and increased hydrophilicity ( 10 – 13 ).…”

“…This makes it difficult for small molecules to bind with sufficiently high energy/affinity. Nevertheless, considerable progress has been made during the last decade, and currently there are many PPI-targeting small molecules in preclinical development [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Two PPI-targeting small molecules have been recently approved by the FDA for clinical applications: venetoclax, targeting a PPI in the B cell lymphoma 2 (BCL-2) family [ 51 , 52 ], and lifitegrast, targeting the LFA-1–ICAM-1 interaction [ 48 , 53 ].…”

Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse

“…However, with regard to these compounds, no biological experiments indicating the immunological activity have been published to date. Interestingly, a novel small molecule dual inhibitor of immune checkpoint PD-L1 and V-domain Ig-containing suppressor of T-cell activation (VISTA), CA-170, was recently investigated in a phase 1 trial of advanced solid tumors and lymphomas (6,10).…”

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

“…An additional approach to target NLRP3 priming could be to disrupt protein‐protein interactions (PPI) with NLRP3 protein binding partners. Recognizing the importance of PPIs to the function of biological systems, medicinal chemists have made considerable progress in their ability to disrupt these interactions with small molecules 133,140 . The development of PPI inhibitors and in particular intracellular ones is challenging.…”

“…The development of PPI inhibitors and in particular intracellular ones is challenging. There are however a number of successful examples such as ABT‐199 (Venetoclax) that targets B‐cell lymphoma 2 (Bcl‐2) protein interactions and is used to treat chronic lymphocytic leukemia 133,140 . Molecules that could disrupt NLRP3 oligomerization, NLRP3‐NEK7 or NLRP3‐ASC interactions would effectively limit NLRP3 activation.…”