SPLINTS: small-molecule protein ligand interface stabilizers

Abstract

Regulatory protein-protein interactions are ubiquitous in biology, and small molecule protein-protein interaction inhibitors are an important focus in drug discovery. Remarkably little attention has been given to the opposite strategy – stabilization of protein-protein interactions, despite the fact that several well-known therapeutics act through this mechanism. From a structural perspective, we consider representative examples of small molecules that induce or stabilize the association of protein domains to inhibit, or alter, signaling for nuclear hormone, GTPase, kinase, phosphatase, and ubiquitin ligase pathways. These SPLINTS (small-molecule protein ligand interface stabilizers) drive interactions that are in some cases physiologically relevant, and in others entirely adventitious. The diverse structural mechanisms employed suggest approaches for a broader and systematic search for such compounds in drug discovery.

Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders

“…Molecular glues refer to small-molecule PPI stabilizers that bind a protein and modify its molecular surface, thus enabling it to recruit a new protein ( Figure 1 ) [ 14 ]. Several examples of molecular glues can be found in nature, including some macrocyclic agents initially thought to act via conventional inhibition.…”

“…The resulting ternary complex of FRB:rapamycin:FKBP12 shows de novo interactions between the FRB domain and FKPB12 in addition to interactions between rapamycin and both proteins [ 19 , 20 ]. The precise mechanism of action is still unknown, but it is suggested that FKB12 may impede access to the mTOR catalytic site [ 14 ].…”

Plasticity in binding confers selectivity in ligand-induced protein degradation

“…Targeted protein degradation refers to small molecule induced ubiquitination and degradation of disease targets, in which a small molecule simultaneously recruits both a ubiquitin E3 ligase and the target protein to be ubiquitinated (Supplementry Fig. 1a); therefore, representing a functional application of chemically induced protein dimerization 8,11 . Clinical proof of concept for targeted protein degradation is provided by the recent discovery that the potent anti-cancer drugs thalidomide, lenalidomide and pomalidomide (collectively known as IMiDs for immuno-modulatory drugs) exert their therapeutic effects through induced degradation of key efficacy targets, such as IKZF1, IKZF3 12–14 , ZFP91 15 , or casein kinase 1 alpha (Ck1α) 16,17 .…”

Structure‐Guided Design of Peptides as Tools to Probe the Protein–Protein Interaction between Cullin‐2 and Elongin BC Substrate Adaptor in Cullin RING E3 Ubiquitin Ligases

“…[2] Thes ignificant roles of CRLs in several biological processes and human diseasesh as rapidly emerged, in particulari nc ancer, where the genes encoding for E3 ligase subunits and their native substrates are often found as oncogenes or tumors uppressors. [3] Currently, much focus is directed towardt argeting E3 CRLs with small molecules, such as inhibitors, to block the ligase activity; [4] molecular glues, to redirect E3 CRL activity toward neo-substrates; [5] and bivalent PROTACs, to induce targeted protein degradation. [6,7] These chemical modalities motivate the growing interest in studying this class of enzymes.W hile E3 inhibitors, molecular glues and PROTACs have been widely reported, to our knowledge there are only af ew examples of small moleculesd eveloped to disrupti nter-subunit assembly within CRLs.…”