Cited by Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo DOI

Christiane Kofink,

Nicole Trainor, Barbara Mair

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 10, 2022

Abstract Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target E3 ligase, resulting in ubiquitylation proteosome-dependent target. In clinic, oral route administration is option choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed achieve orally bioavailable that selectively degrade BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, allow vivo evaluation synthetic lethality concept dependency SMARCA4-deficient cancers. Here we outline structure- property-guided approaches led VHL-recruiting degraders. Our tool compound, ACBI2, shows selective SMARCA4 ex human whole blood assays efficacy cancer models. This study demonstrates feasibility broadening ligase physicochemical space can be utilised achieving with

Language: Английский

Citations

148

Theranostic Fluorescent Probes DOI

Amit Sharma, Peter Verwilst, Mingle Li

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(5), P. 2699 - 2804

Published: Feb. 29, 2024

The ability to gain spatiotemporal information, and in some cases achieve control, the context of drug delivery makes theranostic fluorescent probes an attractive intensely investigated research topic. This interest is reflected steep rise publications on topic that have appeared over past decade. Theranostic probes, their various incarnations, generally comprise a fluorophore linked masked drug, which released as result certain stimuli, with both intrinsic extrinsic stimuli being reported. release then signaled by emergence signal. Importantly, use appropriate fluorophores has enabled not only this emerging fluorescence marker for but also provided modalities useful photodynamic, photothermal, sonodynamic therapeutic applications. In review we highlight recent work particular focus are activated tumor microenvironments. We summarize efforts develop other applications, such neurodegenerative diseases antibacterials. celebrates diversity designs reported date, from discrete small-molecule systems nanomaterials. Our aim provide insights into potential clinical impact still-emerging direction.

Language: Английский

Citations

139

Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders DOI

Claudia J. Diehl, Alessio Ciulli

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(19), P. 8216 - 8257

Published: Jan. 1, 2022

This review provides a comprehensive overview of the structure-based design small-molecule VHL ligands and their applications as inhibitors E3 ligase recruiting moieties in PROTAC degraders.

Language: Английский

Citations

127

Proximity-Based Modalities for Biology and Medicine DOI

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

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders DOI

Keith R. Hornberger, Erika Araujo

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(12), P. 8281 - 8287

Published: June 6, 2023

Heterobifunctional PROTAC degraders are gaining attention as a differentiated therapeutic modality with the potential for oral dosing in clinic. Belonging to beyond Rule of Five domain physicochemical property space, we have sought understand determinants absorption this class molecules rapid development novel agents. We collected large data set from that been dosed orally and intravenously rats estimate fraction absorbed dosing. Through estimation, effects differential hepatic clearance normalized, allowing better assessment absorption. demonstrate less permissive than mice. The properties then evaluated once compounds rank-ordered by absorbed. derive suggested design constraints on associated higher probability being

Language: Английский

Citations

Delivering on the promise of protein degraders DOI

Matthew N. O’Brien, Suman Luthra, Matthew F. Brown

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(5), P. 410 - 427

Published: Feb. 21, 2023

Language: Английский

Citations

Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection DOI

Daniel H. O’Donovan, Claudia De Fusco, Lara Kuhnke

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2347 - 2360

Published: Feb. 8, 2023

For oral drugs, medicinal chemists aim to design compounds with high bioavailability, of which permeability is a key determinant. Taking advantage >2000 tested in rat bioavailability studies and >20,000 Caco2 assays at Bayer, we have examined the molecular properties governing permeability. In addition classical parameters such as logD weight, also investigated relationship between calculated pKa We find that neutral retain up weight limit 700, while stronger acids bases are restricted weights 400–500. investigate trends for common hydrogen bond donors acceptors, polar surface area, aromatic ring count, rotatable bonds, including exceed Lipinski’s rule five (Ro5). These property–structure relationships combined provide guidelines bioavailable drugs both traditional “beyond 5” (bRo5) chemical space.

Language: Английский

Citations

Advancing Strategies for Proteolysis-Targeting Chimera Design DOI

Minglei Li, Ying Zhi, Bo Liu

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2308 - 2329

Published: Feb. 14, 2023

Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter antitumor drug development, marked significant advances over recent years. Herein, we describe developments PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss opportunities challenges for research.

Language: Английский

Citations

Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape DOI

Edward Price, Manuel Weinheimer,

Alexey Rivkin

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(7), P. 5683 - 5698

Published: March 18, 2024

Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize for rule five (Ro5) compounds; beyond (bRo5) necessitate advanced tools like the experimental measure exposed polarity (EPSA) AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS EPSA against ∼1000 compounds with human data ∼10,000 tool (∼1000 proteolysis targeting chimeras or PROTACs, ∼7000 Ro5s, ∼2000 bRo5s) revealed new patterns trends. We introduced a high-throughput "polarity reduction" descriptor: ETR, EPSA-to-topological polar surface area (TPSA) ratio, highlights unique bRo5 PROTAC subsets specialized design strategies effective absorption. Our guidelines refine by providing innovative vitro approaches, enhancing property optimization, enabling accurate predictions intestinal complex domain.

Language: Английский

Citations

Characteristic roadmap of linker governs the rational design of PROTACs DOI

Yawen Dong, Tingting Ma, Ting Xu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4266 - 4295

Published: April 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Language: Английский

Citations