Protein–Protein Interaction Inhibitors

Abstract

The study of cellular mechanisms of cancer growth and survival has revealed a complex web of signalling pathways that produce the 'hallmarks of cancer'. A number of critical cellular signalling nodes have been characterised from which many new drug targets have been proposed. A number of these nodes are regulated by protein-protein interactions, and so present attractive, if challenging, targets for drug discovery. Drug discovery efforts towards three PPI families have resulted in clinically investigated drugs: i.e. Bcl-2 family inhibitors, MDM2-p53 inhibitors and IAP inhibitors. The discovery and optimisation of these drug classes are detailed in this chapter.

Discovery of MK-4688: an Efficient Inhibitor of the HDM2–p53 Protein–Protein Interaction

“…In general, the development of orally bioavailable, drug-like PPI inhibitors has been challenging. The large, flat, and hydrophobic surfaces inherent to the interface between proteins can lead to the design of inhibitors that are larger and more lipophilic than typical oral drugs. , These molecular properties have been associated with high doses and variable pharmacokinetics (PK) in the clinic, and a reduced probability of successfully reaching the market. − In recent years, there has been significant progress in the discovery of PPI inhibitors with increasing “drug-likeness” that highlights how specific features inherent to some PPI interfaces (hot spots) can lead to higher probability of success. ,− The HDM2–p53 interaction is primarily mediated through a hydrophobic interface, where residues Phe19, Trp23, and Leu26 located on an N-terminal α helix of p53 fit into known hydrophobic pockets on the HDM2 protein surface . Furthermore, it has been shown that inhibitors can interrupt the HDM2–p53 PPI by binding within these hot-spot hydrophobic pockets. − Despite this feature of the PPI interface, the pioneering HDM2 inhibitors in clinical development displayed high lipophilicity, a high molecular weight (MW), and required high doses for efficacy that limited their progression.…”

“…allowed late-stage introduction of a variety of substituents at C6. Specifically, 20 could be transformed into final compounds (22) in three steps consisting of a Suzuki reaction, followed by a two-step oxadiazolone formation. SAR in the Phe19 Pocket.…”

Binding affinity optimization and structural evaluation of designed antibodies against PD-1 and PD-L1 as critical immune checkpoints involved in cancer treatment

“…Protein-protein interactions (PPIs) regulate biological processes in cells, therefore targeting PPIsusing inhibitors could in uence cell functions. PPIs inhibitors are currently becoming more popular and are recognized as a novel treatment strategy that helps develop new drug generations 10,11 . The binding of PD-1 to PD-L1 is an aberrant PPI associated with cancer, which is di cult to target therapeutically 12 .…”

In Silico Peptide-Directed Ligand Design Complements Experimental Peptide-Directed Binding for Protein-Protein Interaction Modulator Discovery

“…Drug discovery for protein-protein interactions (PPIs) has made huge advances in the last decade, making strides to shed the "undruggable" label. The application of fragment based drug discovery [1][2][3] and high throughput screening 4,5 has resulted in many compounds undergoing clinical trials, [6][7][8][9] and the approval of venetoclax in 2016. 10 The methods have proven to be effective, but remain available only to pharmaceutical companies and specially equipped laboratories.…”