Biochemical Principles of Targeted Protein Degradation

Agafonov, Roman V.; Deibler, Richard W.; Elam, W. Austin; Patel, Joe; Fisher, Stewart L.

doi:10.1002/9781119774198.ch10

Cited by 1 publication

(2 citation statements)

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“…75 Furthermore, enhanced catalytic activity leads to a reduced hook effect, resulting from optimal ternary complex formation. 76 As mentioned for the BTK PROTAC NX-5948, catalytic effects may have furnished the degrader with greater resilience to binding site mutations that reduce target occupancy. Recently, our group validated this hypothesis by using an in-cell ALK occupancy reporter assay to drive the design of catalytic EML4-ALK PROTACs.…”

Section: Pk/pd and Pharmacological Biomarkersmentioning

confidence: 99%

“…An important feature of heterobifunctional degraders is that at high concentrations they achieve relatively higher occupancy of the individual E3 or POI alone, which competes with ternary complex formation, resulting in bell‐shaped dose response curves, often referred to as the “hook effect.” 74 However, it is unlikely that the effect manifests itself in vivo because the high concentrations required to observe such high occupancy are only fleetingly achieved, if at all 75 . Furthermore, enhanced catalytic activity leads to a reduced hook effect, resulting from optimal ternary complex formation 76 . As mentioned for the BTK PROTAC NX‐5948, catalytic effects may have furnished the degrader with greater resilience to binding site mutations that reduce target occupancy.…”

Section: Key Challenges and Opportunitiesmentioning

confidence: 99%

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Clinical Translation of Targeted Protein Degraders

Kong

Jones

2023

Clin Pharma and Therapeutics

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Targeted protein degradation (TPD) has emerged as a potentially transformational therapeutic modality with considerable promise. Molecular glue degraders remodel the surface of E3 ligases inducing interactions with neosubstrates resulting in their polyubiquitination and proteasomal degradation. Molecular glues are clinically precedented and have demonstrated the ability to degrade proteins‐of‐interest (POIs) previously deemed undruggable due to the absence of a traditional small molecule binding pocket. Heterobifunctional proteolysis targeting chimeras (PROTACs) possess ligands for an E3 complex and the POIs, which are chemically linked together, and similarly hijack the ubiquitin machinery to deplete the target. There has been a recent surge in the number of degraders entering clinical trials, particularly directed toward cancer. Nearly all utilize CRL4CRBN as the E3 ligase, and a relatively limited diversity of POIs are currently targeted. In this review, we provide an overview of the degraders in clinical trials and provide a perspective on the lessons learned from their development and emerging human data that will be broadly useful to those working in the TPD field.

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Section: Pk/pd and Pharmacological Biomarkersmentioning

confidence: 99%