Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs DOI Creative Commons

Miriam Girardini,

Chiara Maniaci, Scott J. Hughes

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 27(12), P. 2466 - 2479

Published: Feb. 22, 2019

The von Hippel-Lindau (VHL) and cereblon (CRBN) proteins are substrate recognition subunits of two ubiquitously expressed biologically important Cullin RING E3 ubiquitin ligase complexes. VHL CRBN also the most popular ligases being recruited by bifunctional Proteolysis-targeting chimeras (PROTACs) to induce ubiquitination subsequent proteasomal degradation a target protein. Using homo-PROTACs, have been independently dimerized their own degradation. Here we report design, synthesis cellular activity VHL-CRBN hetero-dimerizing PROTACs featuring diverse conjugation patterns. We found that active compound 14a induced potent, rapid profound preferential over in cancer cell lines. At lower concentrations, weaker was instead observed. This work demonstrates proof concept designing hijack different against each other, highlights powerful generalizable proximity-induced strategy achieve knockdown.

Language: Английский

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives DOI Creative Commons
Lei Zhong, Yueshan Li, Liang Xiong

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: May 31, 2021

Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since first tyrosine kinase inhibitor imatinib was approved enter market by US Food Drug Administration (FDA) 2001, an increasing number of small-molecule been developed for treatment malignancies. By December 2020, 89 antitumor FDA National Medical Products (NMPA) China. Despite great progress, anti-cancer still face many challenges, such as a low response rate drug resistance. To better promote development we conducted comprehensive review according target classification. We present all well important candidates clinical trials each target, discuss current provide insights perspectives research drugs.

Language: Английский

Citations

1143
PROTACs: great opportunities for academia and industry DOI Creative Commons
Xiuyun Sun, Hongying Gao, Yiqing Yang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Dec. 24, 2019

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic limited number drug targets, which presently only 20-25% all protein targets that currently being studied. Moreover, focus current explorations their enzymatic functions, ignores functions from scaffold moiety. As promising appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both academia industry for finding available approaches to solve above problems. PROTACs regulate function by degrading target proteins instead inhibiting them, providing more sensitivity drug-resistant greater chance affect nonenzymatic functions. been proven show better selectivity compared classic inhibitors. can be described as chemical knockdown approach with rapidity reversibility, presents new different biology other gene editing tools avoiding misinterpretations arise potential genetic compensation and/or spontaneous mutations. PRTOACs widely explored throughout world outperformed not cancer diseases, but also immune disorders, viral infections neurodegenerative diseases. present very powerful crossing hurdles discovery tool development biology, efforts needed gain get deeper insight into efficacy safety clinic. More binders E3 ligases applicable developing waiting exploration.

Language: Английский

Citations

513
PROTACs: An Emerging Therapeutic Modality in Precision Medicine DOI Creative Commons

Dhanusha A. Nalawansha,

Craig M. Crews

Cell chemical biology, Journal Year: 2020, Volume and Issue: 27(8), P. 998 - 1014

Published: Aug. 1, 2020

Language: Английский

Citations

335
Challenges and Opportunities in Cancer Drug Resistance DOI
Richard A. Ward, Stephen E. Fawell,

Nicolas Floc’h

et al.

Chemical Reviews, Journal Year: 2020, Volume and Issue: 121(6), P. 3297 - 3351

Published: July 21, 2020

There has been huge progress in the discovery of targeted cancer therapies recent years. However, even for most successful and impactful drugs which have approved, both innate acquired mechanisms resistance are commonplace. These emerging studied intensively, enabled drug scientists to learn how it may be possible overcome such subsequent generations treatments. In some cases, novel candidates able supersede previously approved agents; other cases they used sequentially or combinations with existing This review summarizes current field terms challenges opportunities that presents scientists, a focus on small molecule therapeutics. As part this review, common themes approaches identified utilized successfully target resistance. includes increase potency selectivity, alternative chemical scaffolds, change mechanism action (covalents, PROTACs), increases blood-brain barrier permeability (BBBP), targeting allosteric pockets. Finally, wider covered as monoclonal antibodies (mAbs), bispecific antibodies, antibody conjugates (ADCs), combination therapies.

Language: Английский

Citations

334
Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges DOI
Scott D. Edmondson, Bin Yang, Charlene Fallan

et al.

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2019, Volume and Issue: 29(13), P. 1555 - 1564

Published: April 20, 2019

Language: Английский

Citations

318
Degradation of proteins by PROTACs and other strategies DOI Creative Commons
Yang Wang, Xueyang Jiang, Feng Feng

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2019, Volume and Issue: 10(2), P. 207 - 238

Published: Aug. 13, 2019

Blocking the biological functions of scaffold proteins and aggregated is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be solution, considering its ability to selectively degrade target proteins. Recent progress in strategy include identification structure first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), ARV-110 has entered clinical trials for treatment prostate cancer 2019. These discoveries strongly proved value strategy. In this perspective, we summarized recent meaningful research PROTAC, including types degradation proteins, preliminary data vitro vivo, new E3 ubiquitin ligases. Importantly, molecular design, optimization application candidate molecules are highlighted detail. Future perspectives development advanced medical fields have also been discussed systematically.

Language: Английский

Citations

255
The PROTAC technology in drug development DOI Creative Commons
Yutian Zou, Danhui Ma, Yinyin Wang

et al.

Cell Biochemistry and Function, Journal Year: 2019, Volume and Issue: 37(1), P. 21 - 30

Published: Jan. 1, 2019

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by molecule. This takes advantage of moiety targeted and recognizing E3 ubiquitin ligase produces hybrid molecule to specifically knock down protein. During first decade, three pedigreed groups worked on development this technology. To date, extended different groups, aiming develop drugs against diseases including cancers. review summarizes contributions PROTAC. Significance study summarized PROTAC readers also presented author's opinions application in tumor therapy.

Language: Английский

Citations

226
Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6 DOI

Baishan Jiang,

Eric S. Wang, Katherine A. Donovan

et al.

Angewandte Chemie International Edition, Journal Year: 2019, Volume and Issue: 58(19), P. 6321 - 6326

Published: Feb. 26, 2019

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, there FDA-approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation their ATP-binding sites, development selective agents has remained elusive. Here, we report imide-based degrader molecules capable degrading both CDK4/6, or selectively either CDK4 CDK6. We were also able tune activity these against Ikaros (IKZF1) Aiolos (IKZF3), which well-established targets degraders. found that in mantle lymphoma lines, combined IKZF1/3 degradation dual produced enhanced anti-proliferative effects compared inhibition, degradation, degradation. In summary, here first compounds inducing CDK6 as tools pharmacologically dissect distinct biological functions.

Language: Английский

Citations

214
Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands DOI
Xin Han, Lijie Zhao,

Weiguo Xiang

et al.

Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 62(24), P. 11218 - 11231

Published: Dec. 5, 2019

Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using antagonist E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in discovery 11 (ARD-266), which effectively induces degradation protein AR-positive (AR+) LNCaP, VCaP, 22Rv1 cell lines DC50 values 0.2–1 nM. ARD-266 capable reducing level by >95% these AR+ reduces AR-regulated gene expression suppression. For first time, we demonstrated that an ligand micromolar affinity its complex can be successfully employed design efficient PROTAC this finding may have significant implication field research.

Language: Английский

Citations

191
Exploring the next generation of antibody–drug conjugates DOI Open Access
Kyoji Tsuchikama, Yasuaki Anami, Summer Y. Y. Ha

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(3), P. 203 - 223

Published: Jan. 8, 2024

Language: Английский

Citations

184