Covalent Modifications & Induced Proximity

To gain deeper insights into the behavior of covalent drugs in physiological settings, we conducted a comparative analysis of a diverse range of approved covalent drugs. Employing chemoproteomics, we investigated their target profiles, while also examining properties commonly assessed during drug development. We anticipate that these findings will serve as a valuable resource for scientists engaged in the development of safe and effective covalent drugs.

Covalent inhibitors offer a differentiated approach to drug-challenging targets with less defined pockets in proximity to nucleophilic amino acids. Here I will discuss progress towards identifying druggable opportunities through chemoproteomic profiling, including a refined model of chemical reactivity and binding affinity to drive covalent occupancy. Examples will be presented of historically challenging target classes, including transcription factors.

Few electrophiles meet the criteria for successful covalent inhibitors. I will present a-substituted methacrylamides and sulfamate acetamides as new classes of electrophiles for Covalent Ligand Directed Release (CoLDR) chemistry. These electrophiles are tunable, and allow functionalization with variable leaving groups with applications to intracellular cargo delivery and novel proximity induction systems. Using ibrutinib as a model, we show how late-stage optimization with CoLDR ‘warheads’ improve its properties.

We developed a covalent BTK PROTAC with sub-nM DC50. This compound only degrades wild type BTK, but not the C481S mutant, indicating that covalent bond formation is required to engage BTK. In-cell target engagement assay showed that the covalent BTK PROTAC is highly permeable with similar permeability to small molecule inhibitors. This case study demonstrates the possibility to develop highly potent single-turnover covalent PROTAC.

Induced proximity is a burgeoning area of research; however, much remains to be learnt about the mechanisms of induced proximity drugs and chemical probes. Here, I discuss chemical protoemic strategies to investigate the mechanism and effects of proximity-inducing molecules.

 Understanding protein-protein interactions can identify new mechanisms for drug discovery and development, particularly for difficult targets where inhibition alone is not sufficient to carry out a therapeutic effect. In this presentation, we show a “twist” on the traditional proximity ligation methods that can be conducive to identifying new modes of actions through complexes and transient interactions.