Targeted protein degradation: advances in drug discovery and clinical practice

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

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Targeting the undruggables—the power of protein degraders

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

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Structural and Physicochemical Features of Oral PROTACs

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 13106 - 13116

Published: July 30, 2024

Achieving oral bioavailability with Proteolysis Targeting Chimeras (PROTACs) is a key challenge. Here, we report the in vivo pharmacokinetic properties mouse, rat, and dog of four clinical PROTACs compare an internally derived data set. We use NMR to determine 3D molecular conformations structural preorganization free solution, introduce new experimental descriptors, solvent-exposed H-bond donors (eHBD), acceptors (eHBA). derive upper limit eHBD ≤ 2 for apolar environments show greater tolerance other (eHBA, polarity, lipophilicity, weight) than Rule-of-5 compliant drugs. Within set structurally related PROTACs, that examples > have much lower those 2. summarize our findings as "Rule-of-oral-PROTACs" order assist medicinal chemists achieve this challenging space.

Language: Английский

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Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(2), P. 1147 - 1167

Published: Jan. 10, 2024

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report design, synthesis, and biological evaluation of series KRASG12D PROTACs by connecting analogues MRTX1133 VHL ligand. Structural modifications linker moiety inhibitor part suggested critical role membrane permeability in degradation activity PROTACs. Mechanism studies with representative compound 8o demonstrated that potent, rapid, selective induced was via VHL- proteasome-dependent manner. This selectively potently suppressed growth multiple mutant cells, displayed favorable pharmacokinetic pharmacodynamic properties mice, showed significant antitumor efficacy AsPC-1 xenograft mouse model. Further optimization appears to be development new chemotherapy KRASG12D-driven cancers as complementary therapeutic strategy inhibition.

Language: Английский

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Applications of protein ubiquitylation and deubiquitylation in drug discovery

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(5), P. 107264 - 107264

Published: April 5, 2024

The ubiquitin-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS involved many important cellular processes. Several new UPS-based technologies, including molecular glue degraders PROTACs (Proteolysis-targeting chimeras) to promote DUBTACs (deubiquitinase-targeting increase stability, have been developed. specifically inducing interactions between different ubiquitin ligases targeted that are not otherwise related, degrade via system; contrast, by proximity of deubiquitinases, created clear degradable polyubiquitin chains stabilize proteins. In this review, we summarize recent research progress degraders, PROTACs, applications. We discuss immunomodulatory drugs (IMiDs), sulfonamides, CDK-targeting development PROTACs. also introduce principle DUBTAC its Finally, propose a few future directions these three technologies related homeostasis.

Language: Английский

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Journey of PROTAC: From Bench to Clinical Trial and Beyond

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" This concept, pioneered by Crews and his team, introduced use small link protein an E3 ubiquitin ligase, inducing ubiquitination subsequent degradation protein. By promoting rather than merely inhibiting function, present novel therapeutic strategy with enhanced specificity effectiveness, especially areas such as cancer neurodegenerative diseases. Since their initial field PROTAC research has rapidly expanded numerous now designed wide range disease-relevant The substantial research, investment, collaboration across academia pharmaceutical industry reflect growing interest PROTACs. Review discusses journey from discovery clinical trials, highlighting advancements challenges. Additionally, recent developments fluorescent photogenic PROTACs, used real-time tracking degradation, presented, showcasing evolving targeted therapy.

Language: Английский

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Self‐Oxygenating PROTAC Microneedle for Spatiotemporally‐Confined Protein Degradation and Enhanced Glioblastoma Therapy

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract Glioblastoma (GBM) is the most aggressive subtype of primary brain tumors, which marginally respond to standard chemotherapy due blood‐brain barrier (BBB) and low tumor specificity therapeutics. Herein, a double‐layered microneedle (MN) patch rationally engineered by integrating acid light dual‐activatable PROteolysis TArgeting Chimera (PROTAC) nanoparticles self‐oxygenating BSA‐MnO 2 (BM) for GBM treatment. The MN administrated at site locally deliver PROTAC prodrug BM nanoparticles. are rapidly released from outer layer specifically activated in acidic intracellular environment cells. Subsequently, near‐infrared activates photosensitizer produce singlet oxygen ( 1 O ) through photodynamic therapy (PDT), thereby triggering spatiotemporally‐tunable degradation bromodomain extraterminal protein 4 (BRD4). nanoparticles, inner MN, serve as an supply station, counteracts hypoxia converting hydrogen peroxide (H into (O ), thus promoting PDT activation. This prodrug‐integrated significantly inhibits growth both subcutaneous orthotopic models. study describes first strategy highly efficient therapy, potentially advancing precise other kinds refractory tumors.

Language: Английский

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Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design

ChemMedChem, Journal Year: 2023, Volume and Issue: 18(8)

Published: Feb. 7, 2023

Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for first time consistent data set allows direct comparison structural variations including those were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design small library highly potent BRD4-degraders comprising different exit vectors. Newly designed degraders showed favorable molecular properties significantly degradation potency compared MZ1.

Language: Английский

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Current advances and development strategies of orally bioavailable PROTACs

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 261, P. 115793 - 115793

Published: Sept. 7, 2023

Language: Английский

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Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders

Drug Metabolism and Disposition, Journal Year: 2023, Volume and Issue: 51(7), P. 792 - 803

Published: April 11, 2023

Targeted protein degraders (TPDs), specifically the bifunctional discussed in this manuscript, consist of two linked ligands for a interest and an E3 ligase, resulting molecules that largely violate accepted physicochemical limits (e.g., Lipinski's Rule Five) oral bioavailability. In 2021, IQ Consortium Degrader DMPK/ADME Working Group undertook survey 18 member nonmember companies working on to understand whether characterization optimization these were different from any other beyond Five (bRo5) compounds. Additionally, group sought identify pharmacokinetic (PK)/absorption, distribution, metabolism, excretion (ADME) areas need further evaluation where additional tools could aid more rapid advancement TPDs patients. The revealed although reside challenging bRo5 space, most respondents focus their efforts delivery. Physicochemical properties required bioavailability generally consistent across surveyed. Many used modified assays address degrader solubility, nonspecific binding), but only half indicated they drug discovery workflows. also suggested scientific investigation central nervous system penetration, active transport, renal elimination, lymphatic absorption, silico/machine learning, human prediction. Based results, concluded TPD does not fundamentally differ compounds requires some modification compared with traditional small proposes generic workflow PK/ADME TPDs.

SIGNIFICANCE STATEMENT

industry survey, article provides understanding current state science pertaining characterizing optimizing targeted degraders, based upon responses by consortium members non-members developing degraders. puts into context differences / similarities methods strategies utilized heterobifunctional conventional molecule drugs.

Language: Английский

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