RAS-targeted therapies: is the undruggable drugged?

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(8), P. 533 - 552

Published: June 11, 2020

Language: Английский

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Spirocyclic Scaffolds in Medicinal Chemistry

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 64(1), P. 150 - 183

Published: Dec. 31, 2020

Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest less planar bioactive compounds has given rise to the development of synthetic methodologies for preparation spirocyclic scaffolds. In this Perspective, we summarize diverse routes obtain systems. impact spirocycles on potency selectivity, including aspect stereochemistry, is discussed. Furthermore, examine changes physicochemical properties as well vitro vivo ADME using selected studies that compare their nonspirocyclic counterparts. conclusion, value medicinal chemistry

Language: Английский

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PROTACs: An Emerging Therapeutic Modality in Precision Medicine

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

Published: Aug. 1, 2020

Language: Английский

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Covalent inhibitors: a rational approach to drug discovery

RSC Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 11(8), P. 876 - 884

Published: Jan. 1, 2020

Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent late 18th century, field has advanced significantly currently about 30% marketed drugs inhibitors. The numerous advantages counteracting initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. aim this review to provide a short historic overview focus on recently developed (2011-2019), including structural aspects examples challenging targets.

Language: Английский

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E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

SLAS DISCOVERY, Journal Year: 2020, Volume and Issue: 26(4), P. 484 - 502

Published: Nov. 4, 2020

Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand treat human disease. A required PROTAC component is ligand binding an E3 ubiquitin ligase, which then joined another protein be degraded via the ubiquitin-proteasome system. The advent nonpeptidic small-molecule ligase ligands, notably for von Hippel-Lindau (VHL) cereblon (CRBN), revolutionized field ushered in design drug-like PROTACs with potent selective degradation activity. first wave drugs now undergoing clinical development cancer, seeking extend repertoire chemistries that allow hijacking ligases improve scope targeted degradation.Here, we briefly review how traditional ligands were discovered, outline approaches have been recently used discover PROTACs. We will take outlook at current future strategies undertaken invoke either target-based screening or phenotypic-based approaches, including use DNA-encoded libraries (DELs), display technologies cyclic peptides, smaller molecular glue degraders, covalent warhead ligands. These ripe expanding space usher other emerging bifunctional modalities proximity-based pharmacology.

Language: Английский

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Advances in covalent kinase inhibitors

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(9), P. 2617 - 2687

Published: Jan. 1, 2020

Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords unique set of advantages as well challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, irreversibly modify proximal nucleophilic residue on via reaction with an electrophile. To date, acrylamide group remains predominantly employed electrophile CKI development, its incorporation majority clinical candidates FDA approved therapies. Nonetheless, recent years considerable efforts ensued characterize alternative electrophiles that exhibit irreversible or reversibly binding mechanisms towards cysteine thiols other amino acids. This review article provides comprehensive overview CKIs reported literature over decade period, 2007-2018. Emphasis is placed rationale behind warhead choice, optimization approach, inhibitor design. Current are also highlighted, addition detailed analysis common trends themes observed within listed data set.

Language: Английский

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The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(15), P. 8408 - 8418

Published: July 14, 2020

The concept of functional groups (FGs), sets connected atoms that can determine the intrinsic reactivity parent molecule and in part are responsible for overall properties molecule, form a foundation within modern medicinal chemistry. In this Article, we analyze occurrence various FGs molecules described chemistry literature over last 40 years show how their development utilization time has varied. popularity not evolved randomly, but instead, clear patterns use evident. Various factors influencing these patterns, including introduction new synthetic methods, novel techniques, strategies applied drug discovery better knowledge molecular affecting success candidate development, discussed.

Language: Английский

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Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries

Nature Biotechnology, Journal Year: 2021, Volume and Issue: 39(5), P. 630 - 641

Published: Jan. 4, 2021

Language: Английский

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The emerging role of mass spectrometry-based proteomics in drug discovery

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(9), P. 637 - 654

Published: March 29, 2022

Language: Английский

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Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 24, 2021

Abstract The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. main protease of (M pro ), critical for viral replication, is a key target therapeutic development. An organoselenium drug called ebselen been demonstrated have potent M inhibition and antiviral activity. We examined the binding modes its derivative in via high resolution co-crystallography investigated their chemical reactivity mass spectrometry. Stronger than ability rescue infected cells were observed number derivatives. A free selenium atom bound with cysteine catalytic dyad revealed crystallographic structures MR6-31-2 suggesting hydrolysis enzyme covalent adduct formation phenolic by-product, confirmed by engagement selenation mechanism suggests wider applications these compounds against other zoonotic beta -corona viruses.

Language: Английский

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