Despite significant progress over the past few decades in developing small molecule therapeutics against drug targets with clearly defined binding sites, the majority of potential targets in human disease do not fit current models of drug discovery. Well-known oncogenic targets such as MYC and ARv7 that function as transcriptional drivers or through other protein-protein interactions are often poorly suited to traditional high-throughput screening or rational design. The targets are frequently disordered when isolated from binding partners or physiological complexes, generally lack obvious binding pockets, and may act through complex signaling pathways. Despite a wealth of data implicating these oncogenes in some of the deadliest forms of cancer, no approved therapeutics exist. Thus, there is a critical need for new approaches to discover drug candidates against these targets.
Transcription Factors: Prototypical Undruggable Targets
Small Molecule Microarray
Kronos Bio’s small molecule microarray (SMM) platform builds on over a decade of research into high-throughput screening strategies for chemical modulators of transcription factors and other historically undruggable targets with potential application for a range of diseases.
Small molecule microarrays contain a library of drug-like small molecules that have been arrayed and immobilized on a solid surface. SMM technology is uniquely suited to identifying modulators of transcription factors and other protein-protein interactions because the screen against a target protein can be conducted in whole cell lysates. A single high-throughput SMM screen in a more physiologically relevant context can probe a target’s entire interactome, potentially identifying compounds that bind or interfere with the target protein directly, disrupt protein-protein complexes, or affect nearest neighbor proteins that may indirectly modulate target activity. This approach is ideally suited for rapid discovery of multiple hits with novel mechanisms of action for modulating historically undruggable targets such as transcription factors.
Targeted Protein Degradation
Targeted protein degradation (TPD) is an emerging therapeutic approach with application in drugging historically undruggable targets. Bifunctional protein degraders bind both a target protein and an E3 ligase. The E3 ligase promotes the transfer of ubiquitin to the target protein, marking the protein for destruction by the proteasome.
Kronos Bio is focused on discovering and developing novel binders to tissue- or tumor-restricted E3 ligases. Creating bifunctional degraders targeting these novel E3 ligases may confer greater selectivity relative to degraders targeting ubiquitously expressed E3 ligases.