08/05/2021: 12:00 PM - 3:00 PM
Targeted protein degradation denotes the ability of a small molecule to catalyze the selective breakdown of a protein of interest via the ubiquitin-proteasome system (UPS). The ability to modulate protein levels offer a novel alternative paradigm to classical inhibitors and has been a major focus for both industrial and academic groups around the world. Structural characterization of these small molecule induced, non-cognate ternary complexes between the E3 ligase and protein of interest has presented unique challenges to advancing structure-based drug design efforts. This session will be dedicated to highlighting the significant structural advances that have been made in interrogating these induced complexes, insights into the structure-activity relationships of the small molecules, and the plasticity of the ligases to selectivity recognize disease relevant targets.
Targeted protein degradation is a relatively new field of drug discovery that is attracting massive global investment in both academic and industrial environments. The ability to trigger the destruction of disease-associated proteins with low molecular weight compounds has massive implications for drug discovery and could lead to numerous medicines. Although the first successes in degradation research were reported 20 years ago, it is over the last 10 years that several key advances took place, including the finding that several approved drugs achieve clinical effects through targeted protein degradation.
Cereblon is a component of the CRL4-CRBN E3 ubiquitin ligase and is the target of the myeloma drugs thalidomide, lenalidomide and pomalidomide. Following the discovery that cereblon directly binds thalidomide, structural studies were critical in understanding the molecular glue mechanism of action. These drugs bind to the surface of cereblon and repurpose the E3 ligase to recruit non-native substrates leading to ubiquitination and degradation. Repurposing of cereblon can be achieved through either heterobifunctional drugs or molecular glue degraders. Molecular glue drugs are lower molecular weight than heterobifunctional drugs and rely more extensively on stabilizing protein-protein interactions. Thalidomide analogs have been extremely well studied as archetypal molecular glues, with crystal structures determined for several cereblon complexes. In addition to cereblon-drug binary complexes, several substrate bound ternary complexes have been solved. A critical 'degron' feature required for substrate recruitment, enabling rational design for optimizing efficacy and selectivity. The degron is found in otherwise unrelated cereblon substrates that share no sequence, fold or functional similarity.
There are an estimated 600 E3 ubiquitin ligases in human cells, indicating considerable potential for the discovery of new molecular glues. In this talk structural studies on the cereblon E3 ligase will be described as a model system for understanding the principles of molecular glue drug discovery.
Small molecule degraders have shown considerable promise as a new pharmacological modality. With the mounting structural information on degrader mediated ligase-substrate interactions we are beginning to understand the rationale for target recruitment and selectivity. This presentation will describe a structural basis for accelerating degrader design.
Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). Our results reveal insights from unique ternary complex structures and show that increased ternary complex stability/rigidity need not always correlate with increased degradation efficiency.
VHL is one of the most widely exploited E3 ligases to induce ubiquitination and subsequent targeted protein degradation. Although many VHL-mediated bifunctional proteolysis-targeting chimeras (PROTACs) are known in the literature, bona fide example of small molecule glue degrader that recruit client protein to interact with VHL remains scant. Here, we report a small molecular glue degrader discovered from protein microarrays. Using several biochemical, biophysical and cellular assays, we demonstrate these compounds induce neo-interactions between VHL and cysteine dioxygenase (CDO1), leading to the polyubiquitination and degradation of CDO1. Structural characterization of this VHL/CDO1/glue ternary complex maps the degron to a composite surface formed by multiple discontiguous regions of hCDO1. Collectively, our studies reveal the mechanism of action of a novel small molecular glue degrader that directly recruits CDO1 to VHL, presenting a new avenue for targeted protein degradation.
, Novartis Institutes for BioMedical Research Walnut Creek, CA
With the exponential growth in the development of targeted protein degraders come significant challenges for the structural biology and computational modelling communities. Numerous examples now exist in the literature of the exquisite SAR possible through modifications of these molecules and this has driven a need to generate atomic level ternary complex information to assist degrader design and elucidate mechanism of action. Here we will present our approach combining biophysical and computational methods to generate weighted models to support medicinal chemistry campaigns.
Ternary complex structures of PROTAC molecules are still rare and difficult to obtain. They capture a snapshot of one of the many conformations thought to be present in solution and perhaps one of the many ligase-target protein orientations that may lead to successful degradation. Integrating various emerging techniques such as SPR, mass photometry, native and HDX-MS may improve the success rate of obtaining structures and add complementary insights. This talk will discuss how best to use these rare snapshots and multiple techniques to improve PROTAC design.