45,075 results match your criteria inhibitors series


Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors.

Eur J Med Chem 2021 Sep 11;226:113845. Epub 2021 Sep 11.

Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China. Electronic address:

To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFR) for use as EGFR kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFR, with an IC value of 4.0 nM and more than 42-fold selectivity for EGFR (IC = 170. Read More

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September 2021

Transforming Type II to Type I c-Met kinase inhibitors via combined scaffold hopping and structure-guided synthesis of new series of 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-one derivatives.

Bioorg Chem 2021 Aug 25;116:105304. Epub 2021 Aug 25.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.

Novel 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-one derivatives 3a-e, 4a-f and 5a-f were designed as Type I c-Met kinase inhibitors based on scaffold hopping of our previous Type II c-Met kinase lead. Target compounds were then synthesized under the guidance of molecular docking analysis to identify the potential inhibitors that fit the binding pocket of c-Met kinase in the characteristic manner as the reported Type I c-Met kinase inhibitors. All synthesized derivatives were evaluated for their c-Met kinase inhibitory activity at 10 µM concentration, where 3d, 5d and 5f displayed >80% inhibition. Read More

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Discovery of novel 2-phenylamino-4-prolylpyrimidine derivatives as TRK/ALK dual inhibitors with promising antitumor effects.

Bioorg Med Chem 2021 Sep 8;47:116396. Epub 2021 Sep 8.

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address:

In order to explore novel TRK and ALK dual inhibitors, a series of 2-phenylamino-4-prolylpyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxicity and enzymatic activities. Delightfully, most compounds were detected moderated to excellent activities in cellular assay. Among them, compound 21 exhibited encouraging cytotoxicity on KM12, H2228 and KARPAS299 cells with IC values of 0. Read More

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September 2021

Robotic-assisted Resection of a Diaphragmatic Metastasis of a Gastrointestinal Stromal Tumor.

Surg Laparosc Endosc Percutan Tech 2021 Sep 17. Epub 2021 Sep 17.

Department of Surgery, Medical College of Wisconsin, Milwaukee, WI.

Gastrointestinal stromal tumors (GISTs) are relatively rare mesenchymal tumors. The treatment of these tumors has drastically changed based on molecular treatment methods, namely tyrosine kinase inhibitors, which have led to impressive survival benefits. While medical management has enhanced patient outcomes, surgery is still the standard of care for stable, completely resectable primary tumors or metastases that are >2 cm. Read More

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September 2021

Utilization of Metabolite Identification and Structural Data to Guide Design of Low-Dose IDO1 Inhibitors.

ACS Med Chem Lett 2021 Sep 18;12(9):1435-1440. Epub 2021 Aug 18.

Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, and Pharmacology, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD). Read More

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September 2021

A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice.

Eur J Med Chem 2021 Sep 13;226:113827. Epub 2021 Sep 13.

Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, 518057, China. Electronic address:

Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Read More

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September 2021

Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA.

Bioorg Chem 2021 Sep 13;116:105339. Epub 2021 Sep 13.

Chemistry Department, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt. Electronic address:

Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. Read More

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September 2021

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase.

J Med Chem 2021 Sep 16. Epub 2021 Sep 16.

Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.

Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor (AS-1763) as a next-generation noncovalent BTK inhibitor. Read More

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September 2021

A low dose rituximab regimen for first-line treatment of acquired haemophilia A.

Eur J Haematol 2021 Sep 16. Epub 2021 Sep 16.

Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston 4029, QLD and Faculty of Medicine, University of Queensland, Herston, 4006, QLD, Australia.

Introduction: Acquired haemophilia A (AHA) is a rare disease caused by the development of autoantibodies against FVIII. Diagnosis involves confirmation of FVIII deficiency and the presence of an inhibitor via the Bethesda assay. Severe bleeding is often managed with bypassing agents such as recombinant factor VII. Read More

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September 2021

Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol.

Front Cardiovasc Med 2021 30;8:712478. Epub 2021 Aug 30.

Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands.

Cardioprotective strategies against ischemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Therefore, maintained efficacy of cardioprotective strategies in the presence of drugs routinely used clinically (e.g. Read More

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Treatment of pulmonary arterial hypertension in children.

Cardiovasc Diagn Ther 2021 Aug;11(4):1144-1159

Department of Pediatric Cardiology and Congenital Heart Diseases, Centre of Child and Adolescent Health, University Hospital Heidelberg, Heidelberg, Germany.

Pulmonary arterial hypertension (PAH) is a devastating illness causing already significant morbidity in childhood. Currently approved treatment options for children comprise the endothelin receptor antagonist bosentan, as well as the phosphodiesterase-5 inhibitor sildenafil. But PAH treatment has advanced significantly over the past decade, and new classes of targeted drug therapies, such as stimulators of the soluble guanylate cyclase (riociguat) or prostacyclin receptor agonists (selexipag), are currently evaluated regarding their efficacy and safety in children, in order to limit off-label use. Read More

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Initial rapidity of tumor growth as a prognostic factor for the therapeutic effect of immune-checkpoint inhibitors in patients with non-small cell lung cancer: evaluation for linear and non-linear correlation.

J Thorac Dis 2021 Aug;13(8):4903-4914

Department of Pulmonary Medicine, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.

Background: Immune-checkpoint inhibitors (ICIs) have been increasingly used for non-small cell lung cancer (NSCLC) treatment in recent years. Although insufficient, the rate of programmed death-ligand 1 expression has been adopted as a predictor of ICI efficacy. We evaluated tumor growth rate as a clinically easy-to-use predictor of the therapeutic effect of ICIs. Read More

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Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics.

Comput Struct Biotechnol J 2021 24;19:4156-4164. Epub 2021 Jul 24.

Department of Medicinal Chemistry, College of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.

Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60's, 90's and 130's helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Read More

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Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity.

ACS Med Chem Lett 2021 Sep 16;12(9):1478-1485. Epub 2021 Aug 16.

Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.

We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with -halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of and . By increasing the electron-withdrawing properties of the -halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against and methicillin-resistant (MRSA) strains. Read More

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September 2021

The Role of Kallikrein 7 in Tumorigenesis.

Curr Med Chem 2021 Sep 14. Epub 2021 Sep 14.

Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang, 443003. China.

Kallikrein 7 (KLK7) is a secreted serine protease with chymotrypsic protease activity. Abnormally high expression of KLK7 is closely related to the occurrence and development of various types of cancer. Therefore, KLK7 has been identified as a potential target for cancer drug development design in recent years. Read More

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September 2021

Do age, fitness and concomitant medications influence management and outcomes of CLL patients treated with ibrutinib?

Blood Adv 2021 Sep 15. Epub 2021 Sep 15.

Niguarda Cancer Center, Niguarda Hospital, Milano, Italy.

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In ibrutinib era it is still unclear whether age, CIRS and ECOG-PS retain their predictive role on treatment vulnerability. Read More

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September 2021

A Step Towards NRF2-DNA Interaction Inhibitors by Fragment-Based NMR Methods.

ChemMedChem 2021 Sep 15. Epub 2021 Sep 15.

Boehringer Ingelheim RCV GmbH & Co KG: Boehringer Ingelheim RCV GmbH und Co KG, Medicinal Chemistry, AUSTRIA.

The NRF2 transcription factor is a key regulator in cellular oxidative stress response, and acts as a tumor suppressor. Aberrant activation of NRF2 has been implicated in promoting chemo-resistance, tumor growth, and metastasis by activating its downstream target genes. Hence, inhibition of NRF2 promises to be an attractive therapeutic strategy to suppress cell proliferation and enhance cell apoptosis in cancer. Read More

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September 2021

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors.

Drug Dev Res 2021 Sep 15. Epub 2021 Sep 15.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Giza, Egypt.

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2-Acetylbenzofuran derivatives 1a,b and 3-acetylindole 1c were condensed with Wittig reagents 2a-d and Wittig-Horner reagents 3a-e to afford the respective 2-ethylidene derivatives 5a-j and 7a-e. Read More

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September 2021

Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase.

Res Pharm Sci 2021 Oct 19;16(5):482-492. Epub 2021 Aug 19.

Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, I.R. Iran.

Background And Purpose: Alzheimer's disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer's disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects.

Experimental Approach: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. Read More

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October 2021

[Research Progress of Immune Checkpoint Inhibitor-associated Myocarditis].

Zhongguo Fei Ai Za Zhi 2021 Sep 15. Epub 2021 Sep 15.

Department of Oncology, The Second Affiliated Hospital of Nanchang University, 
Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang 330006, China.

Immune checkpoint inhibitors (ICIs) is a negative regulatory factor antibody, which activates T cells to play an anti-tumor effect in immunotherapy, and can also cause immune-related adverse responses, thereby inducing a series of immune related adverse events (irAEs). Among these irAEs, although the incidence of ICIs-related myocarditis is very low, the fatality rate is significantly higher than other adverse reactions, close to 50%. Clinicians should be vigilant when applying ICIs, but the pathogenesis of ICIs-related myocarditis is still unclear. Read More

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September 2021

Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli β-glucuronidase inhibitors.

Bioorg Chem 2021 Aug 27;116:105306. Epub 2021 Aug 27.

College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China. Electronic address:

Gut microbial β-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1-15) were synthesized and evaluated for their inhibitory effects against Escherichia coli β-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC values ranging from 0. Read More

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Impact of regulatory interventions to restrict the combined use of renin-angiotensin system-acting agents: A Danish nationwide drug utilisation study.

Br J Clin Pharmacol 2021 Sep 13. Epub 2021 Sep 13.

Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.

This study aimed to evaluate the impact of the risk minimisation measures issued by the European Medicines Agency in 2014 to restrict the combined use of renin-angiotensin system (RAS) agents in Denmark. Data from the Danish National Prescription Registry covering all medications dispensed during January 2008-December 2018 was used. The outcome was monthly prevalence of patients co-dispensed RAS-acting agents. Read More

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September 2021

Synthesis and biological evaluation of selective histone deacetylase 6 inhibitors as multifunctional agents against Alzheimer's disease.

Eur J Med Chem 2021 Sep 3;225:113821. Epub 2021 Sep 3.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, PR China. Electronic address:

Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor. Read More

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September 2021

Expanded Ensemble Methods Can be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies.

J Chem Theory Comput 2021 Sep 13. Epub 2021 Sep 13.

Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.

Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. Read More

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September 2021

Design and synthesis of phenoxymethybenzoimidazole incorporating different aryl thiazole-triazole acetamide derivatives as α-glycosidase inhibitors.

Mol Divers 2021 Sep 13. Epub 2021 Sep 13.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

A novel series of phenoxymethybenzoimidazole derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested compounds displayed promising α-glycosidase inhibitory potential with IC values in the range of 6.31 to 49. Read More

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September 2021

Direct Blood Pressure-Independent Anti-Fibrotic Effects by the Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone in Progressive Models of Kidney Fibrosis.

Am J Nephrol 2021 Aug 30;52(7):588-601. Epub 2021 Aug 30.

Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany.

Introduction: The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in chronic kidney disease patients with type 2 diabetes. Precise molecular mechanisms responsible for these benefits are incompletely understood. Here, we investigated potential direct anti-fibrotic effects and mechanisms of nonsteroidal MR antagonism by finerenone or SGLT2 inhibition by empagliflozin in 2 relevant mouse kidney fibrosis models: unilateral ureter obstruction and sub-chronic ischemia reperfusion injury. Read More

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Acridine derivatives as inhibitors/poisons of topoisomerase II.

Authors:
Maria Kozurkova

J Appl Toxicol 2021 Sep 12. Epub 2021 Sep 12.

Department of Biochemistry, Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Kosice, Slovak Republic.

The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity. Read More

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September 2021

Understanding Hyaluronan Receptor (CD44) Interaction, HA-CD44 Activated Potential Targets in Cancer Therapeutics.

Adv Pharm Bull 2021 May 15;11(3):426-438. Epub 2020 Jul 15.

Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia.

Cancer is a complex mechanism involving a series of cellular events. The glycoproteins such as hyaluronan (HA) are a significant element of extracellular matrix (ECM), involve in the onset of cancer developmental process. The pivotal roles of HA in cancer progression depend on dysregulated expression in various cancer. Read More

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Preclinical and clinical progress for HDAC as a putative target for epigenetic remodeling and functionality of immune cells.

Int J Biol Sci 2021 3;17(13):3381-3400. Epub 2021 Aug 3.

Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, Beijing, China.

Genetic changes are difficult to reverse; thus, epigenetic aberrations, including changes in DNA methylation, histone modifications, and noncoding RNAs, with potential reversibility, have attracted attention as pharmaceutical targets. The current paradigm is that histone deacetylases (HDACs) regulate gene expression via deacetylation of histone and nonhistone proteins or by forming corepressor complexes with transcription factors. The emergence of epigenetic tools related to HDACs can be used as diagnostic and therapeutic markers. Read More

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