Cited by Miniaturized Click Chemistry and Direct Screening Facilitate the Discovery of Triazole Piperazine SARS-CoV-2 Mpro Inhibitors with Improved Metabolic Stability

Constructing triazole-modified quinazoline derivatives as selective c-MYC G-quadruplex ligands and potent anticancer agents through click chemistry DOI

Jiong-Heng Cai,

Dan-Yan Yang,

Junjie Zhang

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107173 - 107173

Published: Feb. 5, 2024

Language: Английский

Citations

Miniaturized Modular Click Chemistry‐enabled Rapid Discovery of Unique SARS‐CoV‐2 M^pro Inhibitors With Robust Potency and Drug‐like Profile DOI

Mianling Yang,

Myoung Kyu Lee, Shenghua Gao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 25, 2024

Abstract The COVID‐19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96‐ well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M pro ) SARS‐CoV‐2. Subsequent direct biological screening identifies novel 1,2,3‐triazole derivatives as robust M with high anti‐SARS‐CoV‐2 activity. Notably, C5N17B demonstrates sub‐micromolar inhibitory potency (IC 50 = 0.12 µM) and excellent activity Calu‐3 cells determined immunofluorescence‐based assay (EC 0.078 µM, no cytotoxicity: CC > 100 µM). shows superior nirmatrelvir 1.95 similar efficacy ensitrelvir 0.11 Importantly, displays activities against several SARS‐CoV‐2 variants (Gamma, Delta, Omicron, EC 0.13 – 0.26 HCoV‐OC43, indicating its broad‐spectrum It is worthy that retains nirmatrelvir‐resistant strains T21I/E166V L50F/E166V mutations 0.15 respectively). Furthermore, favorable pharmacokinetic properties. Crystallography studies reveal a unique, non‐covalent multi‐site binding mode. conclusion, these findings substantiate potential up‐and‐coming drug candidate for clinical therapy.

Language: Английский

Citations

Augmenting the Anti‐Leukemic Activity of the BCL‐2 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL‐2/HDAC1 and Dual BCL‐2/HDAC6 Inhibitors DOI

Alexandria M. Chan,

Christian Eberly,

Brandon Drennen

et al.

Drug Development Research, Journal Year: 2025, Volume and Issue: 86(3)

Published: May 1, 2025

ABSTRACT Motivated by the anti‐leukemic synergy between histone deacetylase (HDAC) inhibitors and FDA‐approved BCL‐2 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster efficacy of clinical drug grafting HDAC1‐selective or HDAC6‐selective motifs onto a solvent‐accessible domain venetoclax. We discovered multiple polypharmacological agents that both retained potent inhibitory activity venetoclax effectively inhibited either HDAC1 HDAC6 excellent (up 80‐fold) selectivities for desired HDAC isoform. In addition, relative parental two lead compounds, BD‐4‐213 AMC‐4‐154 , exhibited superior activities against acute myeloid leukemia cell line MV4;11 an engineered overexpress BCL‐2. Annexin‐V assay results confirmed on‐target mechanism apoptosis these novel chimeric molecules. Efforts further boost binding affinities and/or proved unsuccessful due synthetic chemistry challenges solubility problems, which may underscore difficulties polypharmacology approaches involving large inhibitor, such as

Language: Английский

Citations

Modular preparation of biphenyl triazoles via click chemistry as non-competitive hyaluronidase inhibitors DOI

Yiman Qin,

G. Li,

Ling Wang

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 146, P. 107291 - 107291

Published: March 16, 2024

Language: Английский

Citations

Discovery of potent HIV-1 NNRTIs by CuAAC click-chemistry-based miniaturized synthesis, rapid screening and structure optimization DOI

Lanlan Jing, Gaochan Wu, Fabao Zhao

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116772 - 116772

Published: Aug. 20, 2024

Language: Английский

Citations

The latest developments in the design and discovery of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV DOI

Junyi Li, Bing Ye, Shenghua Gao

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 18

Published: Oct. 13, 2024

Introduction This review encapsulates the recent strides in development of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment, focusing on novel structural designs that promise to overcome limitations existing therapies, such as drug resistance and toxicity.

Language: Английский

Citations

Slow-Binding and Covalent HDAC Inhibition: A New Paradigm? DOI

Yasir S. Raouf, Carlos Moreno–Yruela

JACS Au, Journal Year: 2024, Volume and Issue: 4(11), P. 4148 - 4161

Published: Oct. 31, 2024

The dysregulated post-translational modification of proteins is an established hallmark human disease. Through Zn2+-dependent hydrolysis acyl-lysine modifications, histone deacetylases (HDACs) are key regulators disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting this family 11 enzymes (HDAC1–11) afforded a first generation broadly acting inhibitors with medicinal applications oncology, specifically cutaneous peripheral T-cell lymphomas multiple myeloma. However, first-generation HDAC often associated weak-to-modest patient benefits, dose-limited efficacies, pharmacokinetic liabilities, recurring clinical toxicities. Alternative inhibitor design to target single avoid toxic Zn2+-binding moieties have not overcome these limitations. Instead, recent literature has seen shift toward noncanonical mechanistic approaches focused on slow-binding covalent inhibition. Such compounds hold potential improving pharmacodynamic profiles through extension drug–target residence time. This perspective aims capture emerging paradigm discuss its improve preclinical/clinical outlook coming years.

Language: Английский

Citations

Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential DOI

Zhen Zhang, Rui Su, Juan Liu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 281, P. 117022 - 117022

Published: Nov. 1, 2024

Language: Английский

Citations

Rapid identification of novel indolylarylsulfone derivatives as potent HIV-1 NNRTIs via miniaturized CuAAC click-chemistry-based combinatorial libraries DOI

Ping Gao,

Shu Song,

Christophe Pannecouque

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

This article presents the rapid identification of novel indolylarylsulfone (IAS) derivatives as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 through a miniaturized click-chemistry-based combinatorial library approach. Utilizing copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC), reliable and biocompatible click chemistry technique, researchers synthesized characterized series IAS derivatives. Several compounds selected

Language: Английский

Citations

Miniaturized Click Chemistry and Direct Screening Facilitate the Discovery of Triazole Piperazine SARS-CoV-2 Mpro Inhibitors with Improved Metabolic Stability DOI

Shenghua Gao,

Letian Song,

Bing Ye

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

The continuous mutational nature of SARS-CoV-2 and its inter-species' similarities emphasize the urgent need to design develop more direct-acting antiviral agents against highly infectious variants. Herein, we report on efficient discovery potent non-covalent non-peptide-derived M

Language: Английский

Citations