Pharmacology of PROTAC Degrader Molecules

Pike, Andy; Guzzetti, Sofia; Gutierrez, Pablo Morentin; Scott, James S.

doi:10.1002/9781119774198.ch11

Cited by 2 publications

(2 citation statements)

References 38 publications

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“…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: Pk/pd and Pharmacological Biomarkersmentioning

confidence: 99%

“…Direct assessment of target occupancy, of the E3 or POI, in preclinical in vivo or clinical studies has not been reported to our knowledge, although these methods are beginning to be used in cell‐based assays 71 . 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 .…”

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%

Section: Key Challenges and Opportunitiesmentioning

confidence: 99%

Clinical Translation of Targeted Protein Degraders

Kong

Jones

2023

Clin Pharma and Therapeutics

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An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions

Guzzetti

Gutierrez

2023

J Pharmacokinet Pharmacodyn

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The value of an integrated mathematical modelling approach for protein degraders which combines the benefits of traditional turnover models and fully mechanistic models is presented. Firstly, we show how exact solutions of the mechanistic models of monovalent and bivalent degraders can provide insight on the role of each system parameter in driving the pharmacological response. We show how on/off binding rates and degradation rates are related to potency and maximal effect of monovalent degraders, and how such relationship can be used to suggest a compound optimization strategy. Even convoluted exact steady state solutions for bivalent degraders provide insight on the type of observations required to ensure the predictive capacity of a mechanistic approach. Specifically for PROTACs, the structure of the exact steady state solution suggests that the total remaining target at steady state, which is easily accessible experimentally, is insufficient to reconstruct the state of the whole system at equilibrium and observations on different species (such as binary/ternary complexes) are necessary. Secondly, global sensitivity analysis of fully mechanistic models for PROTACs suggests that both target and ligase baselines (actually, their ratio) are the major sources of variability in the response of non-cooperative systems, which speaks to the importance of characterizing their distribution in the target patient population. Finally, we propose a pragmatic modelling approach which incorporates the insights generated with fully mechanistic models into simpler turnover models to improve their predictive ability, hence enabling acceleration of drug discovery programs and increased probability of success in the clinic.

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Pharmacology of PROTAC Degrader Molecules

Cited by 2 publications

References 38 publications

Clinical Translation of Targeted Protein Degraders

Clinical Translation of Targeted Protein Degraders

An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions

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