Molecular Glue-Mediated Targeted Protein Degradation: A Novel Strategy in Small-Molecule Drug Development DOI Creative Commons
Xueqiang Tan, Zuyi Huang, Hairun Pei

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(9), P. 110712 - 110712

Published: Aug. 23, 2024

Small-molecule drugs are effective and thus most widely used. However, their applications limited by reliance on active high-affinity binding sites, restricting target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable inducing protein-protein interactions (PPIs). This opens avenues to conventionally undruggable proteins, overcoming limitations seen in conventional drugs. Molecular glues play key role targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) glue degraders recently emergent lysosome techniques like extracellular proteins through the asialoglycoprotein receptors (MoDE-As) macroautophagy (MADTACs). These enable an innovative strategy for prolonged inhibition pathology-associated proteins. review provides overview them, emphasizing clinical potential guiding development molecular-glue-mediated TPD techniques.

Language: Английский

Targeted protein degradation: from mechanisms to clinic DOI
Jonathan M. Tsai, Radosław P. Nowak, Benjamin L. Ebert

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 740 - 757

Published: April 29, 2024

Language: Английский

Citations

98
Proximity-Based Modalities for Biology and Medicine DOI Creative Commons
Xingui Liu, Alessio Ciulli

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(7), P. 1269 - 1284

Published: July 14, 2023

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of processes high selectivity has the potential to substantially expand target space. A plethora proximity-based modalities proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines mechanisms molecules based on induced proximity, including protein degraders, blockers, stabilizers, inducers post-translational modifications, agents cell therapy, discusses challenges that field must address mature unlock translation in biology medicine.

Language: Английский

Citations

89
Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation DOI Creative Commons
Ryan P. Wurz, Huan Rui,

Ken Dellamaggiore

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 13, 2023

Abstract Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design PROTACs is challenging; multiple steps involved in PROTAC-induced make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and by employing von Hippel–Lindau (VHL) recruiting for two different target proteins, SMARCA2 BRD4. Ternary-complex attributes activity parameters are evaluated varying components PROTAC’s architecture. Ternary binding affinity cooperativity correlates well with potency initial rates degradation. Additionally, develop ternary-complex structure modeling workflow calculate total buried surface area at interface, which agreement measured affinity. Our findings predictive framework guide potent degraders.

Language: Английский

Citations

53
The emerging role of PI3K inhibitors for solid tumour treatment and beyond DOI
Carmen Belli,

Matteo Repetto,

Santosh Anand

et al.

British Journal of Cancer, Journal Year: 2023, Volume and Issue: 128(12), P. 2150 - 2162

Published: March 13, 2023

Language: Английский

Citations

48
Navigating the ERK1/2 MAPK Cascade DOI Creative Commons
Ana Martín-Vega, Melanie H. Cobb

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1555 - 1555

Published: Oct. 20, 2023

The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all types. Notably, ERK1/2 are implicated in specific context-dependent manner as stem cells pancreatic β-cells. Alterations the different components of this result dysregulation effector kinases which communicate with hundreds substrates. Aberrant activation contributes to range disorders, cancer. This review provides an overview structure, activation, regulation, mutational frequency tiers cascade; particular focus on ERK1/2. We highlight importance scaffold proteins that contribute kinase localization coordinate interaction dynamics substrates, activators, inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues field.

Language: Английский

Citations

43
Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies DOI Open Access
Daniel Robbins, Mark Noviski,

Ying Siow Tan

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(4), P. 2321 - 2336

Published: Feb. 1, 2024

Bruton's tyrosine kinase (BTK), a member of the TEC family kinases, is an essential effector B-cell receptor (BCR) signaling. Chronic activation BTK-mediated BCR signaling hallmark many hematological malignancies, which makes it attractive therapeutic target. Pharmacological inhibition BTK enzymatic function now well-proven strategy for treatment patients with these malignancies. We report discovery and characterization NX-2127, degrader concomitant immunomodulatory activity. By design, NX-2127 mediates degradation transcription factors IKZF1 IKZF3 through molecular glue interactions cereblon E3 ubiquitin ligase complex. degrades common resistance mutants, including BTKC481S. orally bioavailable, exhibits in vivo across species, demonstrates efficacy preclinical oncology models. has advanced into first-in-human clinical trials achieves deep sustained following daily oral dosing at 100 mg.

Language: Английский

Citations

42
Molecular glues for protein-protein interactions: Progressing toward a new dream DOI Creative Commons
Markella Konstantinidou, Michelle R. Arkin

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(6), P. 1064 - 1088

Published: May 2, 2024

SummaryThe modulation of protein-protein interactions with small molecules is one the most rapidly developing areas in drug discovery. In this review, we discuss advances over past decade (2014–2023) focusing on molecular glues (MGs)—monovalent that induce proximity, either by stabilizing native or inducing neomorphic interactions. We include both serendipitous and rational discoveries describe different approaches were used to identify them. classify compounds three main categories: degradative MGs, non-degradative MGs PPI stabilizers, self-association. Diverse, illustrative examples structural data are described detail, emphasizing elements recognition cooperative binding at interface fundamental for a MG mechanism action.Graphical abstract

Language: Английский

Citations

31
Discovery of fully synthetic FKBP12-mTOR molecular glues DOI Creative Commons

Robin C. E. Deutscher,

Christian Meyners,

Maximilian L. Repity

et al.

Chemical Science, Journal Year: 2025, Volume and Issue: 16(10), P. 4256 - 4263

Published: Jan. 1, 2025

Molecular glues are a new drug modality with the potential to engage otherwise undruggable targets. However, rational discovery of molecular for desired targets is major challenge and most known have been discovered by serendipity. Here we present first fully synthetic FKBP12-mTOR glues, which were from FKBP-focused, target-unbiased ligand library. Our biochemical screening >1000 in-house FKBP ligands yielded one hit that induced dimerization FKBP12 FRB domain mTOR. The crystal structure ternary complex revealed targeted similar surface on compared natural product rapamycin but radically different interaction pattern. Structure-guided optimization improved potency 500-fold, led compounds initiate FKBP12-FRB formation in cells. results show targeting flat surfaces can be focused support use as versatile presenter protein glues.

Language: Английский

Citations

3
Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies DOI Creative Commons
Elisa Uliassi, María Laura Bolognesi, Andrea Milelli

et al.

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(3), P. 654 - 672

Published: Feb. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Language: Английский

Citations

2
Protein–protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction DOI Creative Commons
Huan Rui,

Kate S. Ashton,

Jaeki Min

et al.

RSC Chemical Biology, Journal Year: 2023, Volume and Issue: 4(3), P. 192 - 215

Published: Jan. 1, 2023

This review surveys molecular glue-induced ternary complexes in the PDB and provides an overview of computational methods that can be utilized to predict them.

Language: Английский

Citations

41