Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Abstract

Diverging from traditional target inhibition, proteasomal protein degradation approaches have emerged as novel therapeutic modalities that embody distinct pharmacological profiles and can access previously undrugged targets. Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, thus lowering administered doses and extending pharmacological effects. With this mechanistic premise, research efforts have advanced the development of small molecule degraders that benefit from stable and increased affinity ternary complexes. However, a holistic framework that evaluates different degradation modes from a catalytic perspective, including focusing on kinetically favored degradation mechanisms, is lacking. In this Outlook, we introduce the concept of an induced cooperativity spectrum as a unifying framework to mechanistically understand catalytic degradation profiles. This framework is bolstered by key examples of published molecular degraders extending from molecular glues to bivalent degraders. Critically, we discuss remaining challenges and future opportunities in drug discovery to rationally design and phenotypically screen for efficient degraders.

Modeling the effect of cooperativity in ternary complex formation and targeted protein degradation mediated by heterobifunctional degraders

“…of cooperativity values, 25 and that over-stabilization of the ternary complex can negatively impact degradation. 7,25,26 Similarly, our model suggests that the optimal range of cooperativity depends on the ubiquitination rate (Fig. 8a).…”

“…Our results explain the experimental observation that efficient HBF degraders may have a wide range of cooperativity values, 25 and that over-stabilization of the ternary complex can negatively impact degradation. 7,25,26…”

“…This may help explain the experimental observation that cooperative ternary complex does not necessarily lead to efficient degradation. 7,30,31…”

PROTAC targeted protein degraders: the past is prologue

“…The second is the ability of the ligase to form degradation-competent ternary complexes between the ligase and POI. Ternary complex formation is a necessary step in the action of a PROTAC molecule, but the degree of ternary complex formation may differ from substrate to substrate 127 ; that is, a ternary complex that forms too efficiently and remains tightly bound will not lead to efficient degradation. Cooperativity of the ternary complex, which is a measure of ternary complex formation in a heterobifunctional system, may be positive or negative between a ligase and a target enabled by a PROTAC molecule 128 and has been shown to lead to degradation in both cases.…”

Atomic-Resolution Prediction of Degrader-mediated Ternary Complex Structures by Combining Molecular Simulations with Hydrogen Deuterium Exchange

“…14,15 The formation of the POI-degrader-ligase ternary complex is central to the targeted protein degradation (TPD) process, but how the formation of the ternary structure impacts protein degradation is still poorly understood, especially given the dynamic nature of the complex. [16][17][18][19] X-ray crystallography of the ternary complex 20 provides a high resolution structure of a single conformational state, but a growing body of evidence suggests that the dynamic nature of the ternary structure may not be accurately represented by this lowest energy crystallization snapshot. For instance, a study of several heterobifunctional degraders found that different degraders displayed different degrees of efficiency, although the corresponding ternary complex structures are nearly identical, thus raising questions about the static structural representations of the ternary complex and degradation efficiency.…”