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1.
Bioorg Med Chem ; 38: 116130, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33848699

RESUMO

Protein-protein interactions (PPIs) are essentially fundamental to all cellular processes, so that developing small molecule inhibitors of PPIs have great significance despite representing a huge challenge. Studying PPIs with the help of peptide motifs could obtain the structural information and reference significance to reduce the difficulty in the development of small molecules. Computational methods are powerful tools to characterize peptide-protein interactions, especially molecular dynamics simulation and binding free energy calculation. Here, we established an affinity prediction model suitable for Casitas B lymphoma-b (Cbl-b) and phosphorylated motif system. According to the affinity data set of multiple truncated peptides, the force field, solvent model, and internal dielectric constant of molecular mechanics/generalized Born surface area (MM/GBSA) method were optimized. Further, we predicted the affinity of the rationally designed new sequences through this model and obtained a new 6-mer motif with a 7-fold increase in affinity and the comprehensive structure-activity relationship. Moreover, we proposed an insight of unexpected activity of the truncated 5-mer peptide and revealed the possible binding mode of the new highly active 6-mer motif by extended simulation. Our results showed that the activity enhancement of the truncated peptide was caused by the acetyl-mediated conformation change. The side chain of Arg and pTyr in the 6-mer motif co-occupied the site p1 to form numerous hydrogen bond interactions and increased hydrophobic interaction formed with Tyr266, leading to the higher affinity. The present work provided a reference to investigate the PPI of Cbl-b and phosphorylated substrates and guided the development of Cbl-b inhibitors.

2.
Free Radic Biol Med ; 168: 129-141, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33794311

RESUMO

The transcription factor nuclear factor erythroid-derived 2-like 2 (NRF2) participates in the activation of the antioxidant cytoprotective pathway and other important physiological processes to maintain cellular homeostasis. The dysregulation of NRF2 activity plays a role in various diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Thus, NRF2 activity is tightly regulated through multiple mechanisms, among which phosphorylation by kinases is critical in the posttranslational regulation of NRF2. For instance, PKC, casein kinase 2, and AMP-activated kinase positively, while GSK-3 negatively regulates NRF2 activity through phosphorylation of different sites. Here, we provide an overview of the phosphorylation regulation pattern of NRF2 and discuss the therapeutic potential of interventions targeting NRF2 phosphorylation.

3.
Med Res Rev ; 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846988

RESUMO

Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein kinases, ribonucleoproteins, steroid hormone receptors, and transcription factors. Although over 30 HSP90 inhibitors have steadily entered clinical trials, further clinical advancement has been restricted by their limited efficacy, inevitable heat shock response, and multiple side-effects, likely induced via an ATP inhibition mechanism. Since both ATP and various co-chaperones play essential roles in the HSP90 chaperone cycle to achieve integrated function, optimal therapeutics require an understanding of the dynamic interactions among HSP90, ATP, and cochaperones. To date, continuous research has promoted the exploration of the cochaperone cell division cycle 37 (CDC37) as a kinase-specific recognizer and has shown that the HSP90-CDC37-kinase complex is particularly relevant in cancers. Indeed, disrupting the HSP90-CDC37-kinase complex, rather than totally blocking the ATP function of HSP90, is emerging as an alternative way to avoid the limitations of current inhibitors. In this review, we first briefly introduce the HSP90-CDC37-kinase cycle and present the currently available approaches for inhibitor development targeting this cycle and provide insights into selective regulation of the kinase clients of HSP90 by more directional ways.

4.
Expert Opin Ther Pat ; : 1-22, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33459063

RESUMO

INTRODUCTION: Stimulator of interferon genes (STING) is a transmembrane protein that localizes in the endoplasmic reticulum. As a crucial adaptor protein in the pathway of sensing cytosolic DNA, STING can regulate innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, activation of the STING signaling pathway is expected to be an efficacious immunotherapeutic tactic for cancer and infectious diseases caused by pathogens. AREAS COVERED: This review summarizes the structures and biological activities of STING agonists published from 2008 to present, the progress in its structural modification of STING agonists, and the development of their clinical study. EXPERT OPINION: STING is an important adaptor protein in the process of triggering the innate immune response to viral infection. So far, substantial STING agonists and inhibitors have been published, and their viable curative effects for diverse diseases prove that STING is a promising therapeutic target.

5.
J Med Chem ; 64(1): 871-889, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33332136

RESUMO

The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In vitro studies indicated that compound 6 directly bound to the NACHT domain of NLRP3 but not to protein pyrin domain (PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly and activation. Compound 6 specifically inhibited the NLRP3 inflammasome activation, but had no effect on the activation of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate sodium (DSS)-induced colitis mouse model, compound 6 exhibited significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo. Therefore, our study provides a potent NLRP3 inflammasome inhibitor, which deserves further structural optimization as a novel therapeutic candidate for NLRP3-driven diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Quinolinas/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Desenho de Fármacos , Feminino , Humanos , Concentração Inibidora 50 , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Quinolinas/metabolismo , Quinolinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
6.
Acta Pharm Sin B ; 10(10): 1904-1925, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33163343

RESUMO

Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.

7.
ACS Med Chem Lett ; 11(11): 2182-2189, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214827

RESUMO

Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to H2O2 was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of H2O2. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.

8.
Eur J Med Chem ; : 112959, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33109397

RESUMO

HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (KD = 5.52 µM) and antiproliferative activity (IC50 = 6.34 µM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.

9.
Expert Opin Ther Pat ; : 1-14, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32990109

RESUMO

INTRODUCTION: Heat shock protein 90 (Hsp90) is one of the most critical chaperones amenable to mediating the folding and maturation of more than 300 client proteins. In normal cells, Hsp90 chaperone cycle is required for regulating multiple cellular processes to maintain homeostasis. However, extremely overexpressed Hsp90 in neoplastic cells results in the dysregulation of client proteins, many of which are indispensable to the accumulation of cancer hallmarks, such as infinite proliferation and increased invasiveness. Consequently, modulation of Hsp90 activity has been considered as a potential strategy for cancer treatment. AREAS COVERED: This review recapitulated recent patents' progress in the development of Hsp90 inhibitors with potent antitumor activities during 2013 to present. Besides, the structural-activity relationships of the patented inhibitors and their structural similarity were also discussed. EXPERT OPINION: Hsp90, as an anticancer target, has been investigated for several decades. The first generation of Hsp90 inhibitors exhibited potent antitumor activities in preclinical trials but were trapped in different phases of clinical trials. The second generation of Hsp90 inhibitors has been identified with increased specificity and security through structure modification. Moreover, these inhibitors may offer opportunities for studies of Hsp90 chaperone and development of Hsp90 inhibition therapy.

10.
J Med Chem ; 63(19): 11149-11168, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32902980

RESUMO

The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure-activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided optimization identified 19a as the most potent inhibitor in this series, with an IC50 of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of 19a. Compound 19a dose-dependently upregulated genes and protein level of Nrf2 as well as its downstream markers and showed protective effects against lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse models. Collectively, we reported here a novel indoline-based Keap1-Nrf2 PPI inhibitor as a potential cardioprotective agent.

11.
Eur J Med Chem ; 207: 112734, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866756

RESUMO

Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor which regulates the constitutive and inducible transcription of a wide array of genes and confers protection against a variety of pathologies. Directly disrupting Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 protein-protein interaction (PPI) has been explored as a promising strategy to activate NRF2. We reported here the first identification of a series of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 inhibitors. Our efforts led to the potent small molecule KEAP1-NRF2 inhibitor, 20c, which exhibited a Kd of 24 nM to KEAP1 and an IC50 of 75 nM in disrupting KEAP1-NRF2 interaction. Subsequent biological studies provided consistent evidence across mouse macrophage cell-based and in vivo models that 20c induced NRF2 target gene expression and enhanced downstream antioxidant and anti-inflammatory activities. Our study not only demonstrated that small molecule KEAP1-NRF2 PPI inhibitors can be potential preventive and therapeutic agents for diseases and conditions involving oxidative stress and inflammation but also enriched the chemical diversity of the KEAP1-NRF2 inhibitors.

12.
J Med Chem ; 63(17): 10045-10060, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787144

RESUMO

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

13.
Drug Discov Today ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32771436

RESUMO

B-cell lymphoma-2 (Bcl-2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. As an antiapoptotic member, myeloid cell leukemin-1 (Mcl-1) can bind with proapoptotic proteins and inhibit apoptosis. Mcl-1 is frequently overexpressed and closely associated with oncogenesis and poor prognosis in several cancers, posing a tremendous obstacle for cancer therapy. Recently, an increasing number of Mcl-1-selective small-molecule inhibitors have entered preclinical studies and advanced into clinical trials. In this review, we briefly introduce the role of Mcl-1 in apoptosis and highlight the recent development of Mcl-1 small-molecule inhibitors.

14.
Redox Biol ; 34: 101565, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422540

RESUMO

Transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), control the redox and metabolic homeostasis and oxidative stress. Inhibitors of Keap1-Nrf2 interaction are promising in oxidative stress related inflammatory diseases but now hit hurdles. By utilizing thiazolidinone moiety to shield the key carboxyl pharmacophore in Keap1-Nrf2 inhibitor, a hydrogen peroxide (H2O2)-responsive prodrug pro2 was developed. The prodrug modification improved the physicochemical properties and cell membrane permeability of the parent drug. Pro2 was stable and stayed inactive under various physiological conditions, while became active by stimulation of H2O2 or inflammation derived reactive oxygen species. Moreover, pro2 exhibited proper pharmacokinetic profile suitable for oral administration and enhanced anti-inflammatory efficiency in vivo. Thus, this novel prodrug approach may not only provide an important advance in the therapy of chronic inflammatory diseases with high level of H2O2, but also offer a fresh solution to improve the drug-like and selectivity issues of Keap1-Nrf2 inhibitors.

16.
Cell Chem Biol ; 27(5): 586-597.e12, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32330443

RESUMO

In this study, we identify the natural product gambogic acid as well as structurally related synthetic xanthones as first-in-class covalent inhibitors of the de novo sphingolipid biosynthesis. We apply chemoproteomics to determine that gambogic acid binds to the regulatory small subunit B of the serine palmitoyltransferase complex (SPTSSB). We then test structurally related synthetic xanthones to identify 18 as an equally potent but more selective binder of SPTSSB and show that 18 reduces sphingolipid levels in situ and in vivo. Finally, using various biological methods, we demonstrate that 18 induces cellular responses characteristic for diminished sphingosine-1-phosphate (S1P) signaling. This study demonstrates that SPTSSB may become a viable therapeutic target in various diseases with pathological S1P signaling. Furthermore, we believe that our compound will become a valuable tool for studying the sphingolipid metabolism and serve as a blueprint for the development of a new generation of sphingolipid biosynthesis inhibitors.

17.
Eur J Med Chem ; 196: 112325, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32330741

RESUMO

N6-methyladenosine (m6A) is the most abundant internal post-transcriptional modification in eukaryotic mRNA. The development of emerging technologies such as m6A-seq, has helped reveal the fundamental role of m6A-RNA in regulation of the mammalian transcriptome. With the identification and advances in the understanding of m6A modulators, the relationship between m6A and human diseases is gradually being revealed. This review summarizes recent progress in the understanding of the role of m6A modulators in human disease and their structural characteristics. We highlight the potential of small-molecule regulators targeting m6A associated proteins as tool molecules and disease treatment options from the medicinal chemistry perspective.

18.
Eur J Med Chem ; 193: 112231, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32193054

RESUMO

p62/SQSTM1 (hereafter as p62) is a stress-inducible cellular protein, which interacts with various signaling proteins to regulate a variety of cellular functions. Growing lines of evidence supported a critical role of p62 in tumorigenesis, and p62 may become a therapeutic target for tumor. In this review, we summarize biological functions of structural domains of p62, reported bioactive molecules targeting p62, and the relationship between p62 and tumorigenesis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Proteína Sequestossoma-1/antagonistas & inibidores , Antineoplásicos/química , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Proteína Sequestossoma-1/metabolismo
19.
J Med Chem ; 63(9): 4644-4654, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32153174

RESUMO

Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.


Assuntos
Compostos Azo/farmacologia , Dasatinibe/análogos & derivados , Dasatinibe/farmacologia , Lenalidomida/análogos & derivados , Lenalidomida/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Compostos Azo/síntese química , Compostos Azo/efeitos da radiação , Linhagem Celular Tumoral , Dasatinibe/efeitos da radiação , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Lenalidomida/efeitos da radiação , Ligantes , Proteólise/efeitos dos fármacos , Estereoisomerismo , Ubiquitina-Proteína Ligases , Ubiquitinação/efeitos dos fármacos , Raios Ultravioleta
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