Kinase inhibitors: the road ahead

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(5), P. 353 - 377

Published: March 16, 2018

Language: Английский

---

Targeted protein degradation: expanding the toolbox

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 18(12), P. 949 - 963

Published: Oct. 30, 2019

Language: Английский

---

PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future

Drug Discovery Today Technologies, Journal Year: 2019, Volume and Issue: 31, P. 15 - 27

Published: Feb. 13, 2019

The majority of currently used therapeutics are small molecule-based and utilize occupancy-driven pharmacology as the mode action (MOA), in which protein function is modulated via temporary inhibition. New modalities that operate using alternative MOAs essential for tapping into "undruggable" proteome. PROteolysis Targeting Chimera (PROTAC) technology provides an attractive new approach utilizes event-driven MOA. Small heterobifunctional PROTACs modulate target levels by hijacking ubiquitin-proteasome system to induce degradation target. Here, we address important milestones development PROTAC technology, well emphasize key findings from this previous year highlight future directions promising drug discovery modality.

Language: Английский

---

PROTACs: great opportunities for academia and industry

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

---

Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

Genes & Development, Journal Year: 2019, Volume and Issue: 33(15-16), P. 960 - 982

Published: May 23, 2019

Precise spatio-temporal control of gene activity is essential for organismal development, growth, and survival in a changing environment. Decisive steps regulation involve the pausing RNA polymerase II (Pol II) early elongation, controlled release paused into productive synthesis. Here we describe factors that enable events trigger Pol gene. We also discuss open questions field concerning stability II, nucleosomes as obstacles to potential roles defining precision dynamics expression.

Language: Английский

---

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Cancer Cell, Journal Year: 2019, Volume and Issue: 36(5), P. 498 - 511.e17

Published: Nov. 1, 2019

Language: Английский

---

Targeted protein degradation: elements of PROTAC design

Current Opinion in Chemical Biology, Journal Year: 2019, Volume and Issue: 50, P. 111 - 119

Published: April 17, 2019

Language: Английский

---

A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader

Cell chemical biology, Journal Year: 2017, Volume and Issue: 25(1), P. 88 - 99.e6

Published: Nov. 9, 2017

Language: Английский

---

Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges

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

Published: April 20, 2019

Language: Английский

---

Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

EBioMedicine, Journal Year: 2018, Volume and Issue: 36, P. 553 - 562

Published: Sept. 14, 2018

There are several challenges towards the development and clinical use of small molecule inhibitors, which currently main type targeted therapies intracellular proteins. PROteolysis-TArgeting Chimeras (PROTACs) exploit ubiquitin-proteasome system to selectively degrade target Recently, small-molecule PROTACs with high potency have been frequently reported. In this review, we summarize emerging characteristics PROTACs, such as inducing a rapid, profound sustained degradation, robust inhibition downstream signals, displaying enhanced selectivity, overcoming resistance inhibitors. tumor xenografts, can significantly attenuate progression. addition, also introduce recent developments PROTAC technology homo-PROTACs. The outstanding advantages over traditional drugs promising preclinical data suggest that has potential greatly promote therapy drugs.

Language: Английский

---