Most Accessed Articles | Identification of New Inhibitors of Mutant Isocitrate Dehydrogenase 2 through Molecular Similarity-based Virtual Screening

Journal Name: Letters in Drug Design & Discovery

Author(s): Lijun Yang, Stefan Pusch, Victoria Jennings, Tianfang Ma, Qihua Zhu, Yungen Xu, Andreas von Deimling*, Xiaoming Zha*.

 

 

 

 

Graphical Abstract:

 

Abstract:

Background: Isocitrate dehydrogenase 2 (IDH2) is an enzyme catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA). Evidences suggest that the specific mutations in IDH2 are critical to the growth and reproduction of severe tumors especially leukemia and glioblastoma. It is found that the inhibitors of mutant IDH2 are promising anti-tumor therapeutics.

Methods: A virtual screening strategy combining molecular similarity search and molecular docking was performed in the binding site of AGI-6780. YL-16, YL-17 and YL-18 were identified as novel mutant IDH2 inhibitors for the reduction of (D)-2-hydroxyglutarate in cellular evaluation. In addition, all the three compounds showed inhibition against IDH2-R172K mutated HEK-293T cells, while weak inhibition against wide-type IDH2 (WT-IDH2) HEK-293T cells.

Results: Significantly, YL-17 showed 84.55% inhibitory activity against IDH2-R172K at 1 µM and weak cytotoxicity to wide-type IDH2 at 50 µM.

Conclusion: YL-17 was highlighted as a new mutant IDH2 inhibitor that could be further developed for therapeutic applications. To read out more, please visit: http://www.eurekaselect.com/164444/article

New Issue | Current Topics in Medicinal Chemistry 19-5

 

Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.

 

 

Articles from the journal Current Topics in Medicinal Chemistry Volume 19, Issue 5:

• Trends in Enzyme Inhibition and Activation in Drug Design – Part II
• Prediction of Drug-Drug Interactions Related to Inhibition or Induction of Drug-Metabolizing Enzymes
• Mycobacterial tuberculosis Enzyme Targets and their Inhibitors
• Design, Synthesis, Evaluation of Antimicrobial Activity and Docking Studies of New Thiazole-based Chalcones
• Synthesis and In Vitro Enzymatic Studies of New 3-Aryldiazenyl Indoles as Promising Helicobacter pylori IMPDH Inhibitors
• Docking Assisted Prediction and Biological Evaluation of Sideritis L. Components with PTP1b Inhibitory Action and Probable Anti-Diabetic Properties

For more details on the article, please visit: https://bit.ly/2PiwVza

Editor’s Choice Article | Design, Microwave Assisted Organic Synthesis and Molecular Docking Studies of Some 4 – (3H)-Quinazolinone Derivatives as Inhibitors of Colchicine- Binding Site of Tubulin

Author(s): Rakesh D. Amrutkar*, Mahendra S. Ranawat.

Journal Name: Current Microwave Chemistry

 

Currently, new chemical entities developed as anticancer agents against tubulin as a protein target. The present work, a quinazoline derivatives were used to design and synthesized by microwave irradiation as an anticancer agent through selective inhibitors of colchicinebinding site of tubulin by the molecular docking of quinazoline derivatives using Schrödinger, LLC, New York, NY, 2017. Read out full article here: http://www.eurekaselect.com/166586/article

 

ARTICLE BY DISEASE – Discovery of Hedgehog Antagonists for Cancer Therapy

ARTICLE BY DISEASE ON “BASAL CELL CARCINOMA“

 

 

Abstract:

Background: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly.

Methods: A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented.

Results: Given the selectivity of small molecules targeting, this pathway for cancer treatment compared to kinase, tubulin or HDAC inhibitors, several such antagonists have been discovered, of which some are in preclinical development and clinical studies. Most of the reported small molecules primarily antagonize the Smoothened receptor although agents targeting Gli1 transcription factor and Shh ligand have also been discovered. Till date, nine Smo antagonists have been evaluated in clinical trials.GDC- 0449/Vismodegib and NVP-LDE225/Erismodegib, were granted approval by the U.S. Food and Drug Administration (U.S. FDA) for the treatment of basal cell carcinoma.

Conclusion: The challenge is to identify agents that target the pathway downstream of Smo and develop strategies to overcome acquired drug resistance to the current Smo inhibitors with deeper understanding of the resistance mechanisms.

 

 

For more details, please visit: http://www.eurekaselect.com/node/150925/article

MOST ACCESSED ARTICLE – Use of human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors in Autoimmune Diseases and New Perspectives in Cancer Therapy

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Author(s): Marco L. Lolli, Stefano Sainas, Agnese C. Pippione, Marta Giorgis, Donatella Boschi, Franco Dosio*.

 

 

 

Abstract:

Background: Human dihydroorotate dehydrogenase (hDHODH, EC 1.3.5.2), a flavindependent mitochondrial enzyme involved in de novo pyrimidine biosynthesis, is a validated therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. However, human DHODH inhibitors have also been investigated as treatment for cancer, parasite infections (i.e. malaria) and viruses as well as in the agrochemicals industry.

Objective: An overview of current knowledge of hDHODH inhibitors and their potential uses in diseases where hDHODH is involved.

Method: This review focuses on recent advances in the development and application of hDHODH inhibitors, specifically covering the patent field, starting from a brief description of enzyme topography and of the strategies usually followed in designing its selective inhibitors.

Results: The most important and well-described novelty is the fact that the discovery, in the autumn of 2016, that hDHODH inhibitors are able to induce in vivo myeloid differentiation has led to the possibility of developing novel hDHODH based treatments for Acute Myelogenous Leukemia (AML).

Conclusion: The review will describe a variety of specific inhibitor classes and conclude on recent and future therapeutic perspectives for this target.

 

READ MORE HERE: http://www.eurekaselect.com/156928

HIGHLIGHTED ARTICLE – TRYPANOTHIONE REDUCTASE: A TARGET FOR THE DEVELOPMENT OF ANTI-TRYPANOSOMA CRUZI DRUGS – MINI-REVIEWS IN MEDICINAL CHEMISTRY

To access the article, please visit: http://www.eurekaselect.com/150897