Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

Ramachandran, Sarath; Ciulli, A.

doi:10.1016/j.sbi.2020.10.009

Cited by 38 publications

(39 citation statements)

References 67 publications

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“…Beyond the ligases already vetted for TPD development, there are several other ubiquitin ligases, enabled by structural and/or validated substrate information, that present a path for the development of small molecules that can ultimately be converted into PROTACs, yet await development as potential PROTACable ligases. Most of these ‘low-hanging fruit’ ligases with structural data have been summarized by two excellent reviews 139 , 140 . However, it must also be mentioned that the definition of low-hanging fruit with respect to structural enablement of ligases has recently been redefined with the ground-breaking publication of artificial intelligence (AI)-driven tertiary structure prediction models from Google/DeepMind 141 and RoseTTAFold 142 .…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,317

996

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Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

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Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,317

996

View full text Add to dashboard Cite

show abstract

“…Isothermal calorimetry (ITC), fluorescence polarization (FP), size exclusion chromatography (SEC), and luminescent proximity assay (i.e., aLISA) are among popular techniques that allow the measurement of these thermodynamic parameters under steady state conditions. 20 In addition to the recent understanding emerging from crystal structures, 21 these biophysical methods have helped define interactions at the protein–protein interface that can display both cooperative behavior and recently appreciated plasticity. Notably, bivalent degrader design can capitalize on protein–protein interactions (i.e., BRD4-VHL, 22 BRD4-CRBN, 23 BTK-CRBN 24 ) to develop more efficient degraders that can also benefit from cooperative behavior ( Figure 2 b).…”

Section: Induced Cooperativity and Pursuit Of Privileged Ternary Complexes For Proteasomal Degradationmentioning

confidence: 99%

Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Rodriguez‐Rivera

Levi

2021

ACS Cent. Sci.

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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.

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“…By solving the crystal structure of MZ1, a Brd4 degrader, with von Hippel-Lindau protein (VHL) and Brd4 bromodomain 2 (Brd4 BD2 ), Gadd et al revealed that the formation of a stable and cooperative E3 ligase-PROTAC-POI ternary complex is important for PROTACs to effectively and specifically degrade their target 5 . This led to the development of a Brd4 PROTAC (AT1) with improved potency and selectivity, demonstrating the power of using structure-guided design to facilitate the development of PROTACs 5,6 . However, the induction of a stable ternary complex by a PROTAC does not always lead to the degradation of its target.…”

mentioning

confidence: 99%

Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

et al. 2021

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PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

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Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

Cited by 38 publications

References 67 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

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