scholarly journals Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020 ◽  
Vol 13 (1) ◽  
pp. 8 ◽  
Author(s):  
Eavan C. McLoughlin ◽  
Niamh M. O’Boyle
Keyword(s):  
Binding Site ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Rational Design ◽  
Clinical Status ◽  
Cancer Therapies ◽  
Colchicine Binding Site ◽  
Anti Cancer ◽  
Recent Developments ◽  
Important Drug

It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

2019 ◽  
Vol 16 (11) ◽  
pp. 1194-1201 ◽  
Author(s):  
Farhad Saravani ◽  
Ebrahim Saeedian Moghadam ◽  
Hafezeh Salehabadi ◽  
Seyednasser Ostad ◽  
Morteza Pirali Hamedani ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Cytotoxic Activity ◽  
Binding Site ◽  
Cell Line ◽  
Cell Lines ◽  
Tubulin Polymerization ◽  
Adenocarcinoma Cell Line ◽  
Adenocarcinoma Cell ◽  
Colchicine Binding Site ◽  
Anti Cancer

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

scholarly journals Research fronts of Chemical Biology

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shanshan Lv
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Chemical Biology ◽  
Rational Design ◽  
Future Research ◽  
Design Strategies ◽  
Binding Assays ◽  
Cellular Mechanisms ◽  
Diagnostic Technologies

Abstract Over the past decades, researchers have witnessed substantially increasing and ever-growing interests and efforts in Chemical Biology studies, thanks to the development of genome and epi-genome sequencing (revealing potential drug targets), synthetic chemistry (producing new medicines), bioorthogonal chemistry (chemistry in living systems) and high-throughput screening technologies (in vitro cell systems, protein binding assays and phenotypic assays). This report presents literature search results for current research in Chemical Biology, to explore basic principles, summarize recent advances, identify key challenges, and provide suggestions for future research (with a focus on Chemical Biology in the context of human health and diseases). Chemical Biology research can positively contribute to delivering a better understanding of the molecular and cellular mechanisms that accompany pathology underlying diseases, as well as developing improved methods for diagnosis, drug discovery, and therapeutic delivery. While much progress has been made, as shown in this report, there are still further needs and opportunities. For instance, pressing challenges still exist in selecting appropriate targets in biological systems and adopting more rational design strategies for the development of innovative and sustainable diagnostic technologies and medical treatments. Therefore, more than ever, researchers from different disciplines need to collaborate to address the challenges in Chemical Biology.

scholarly journals Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase

2020 ◽  
Author(s):  
Thomas Lanyon-Hogg ◽  
Markus Ritzefeld ◽  
Leran Zhang ◽  
Balazs Pogranyi ◽  
Milon Mondal ◽  
...  
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Drug Targets ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Inhibitory Potency ◽  
Interaction Sites ◽  
Small Molecule Inhibition ◽  
Membrane Bound ◽  
Hedgehog Acyltransferase

AbstractThe mammalian membrane-bound O-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitor IMP-1575, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed via kinetic analysis. Our results provide an optimal HHAT inhibitor IMP-1575 (Ki = 38 nM) and a strategy for mapping of interaction sites in MBOATs.

Recent developments in the synthesis and anti-cancer activity of acridine and xanthine-based molecules

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Sasadhar Majhi
Keyword(s):  
Biological Properties ◽  
New Drugs ◽  
Cancer Therapies ◽  
Cytotoxic Effects ◽  
Biological Communities ◽  
Design And Synthesis ◽  
Anti Cancer ◽  
Recent Developments ◽  
Abnormal Cells ◽  
Cancer Activity

Abstract Cancer is the uncontrolled growth and development of abnormal cells which is a major cause of death in both advanced and emerging countries. Although currently chemotherapy is most broadly used among an extensive range of anti-cancer therapies, it includes many demerits, such as highly toxic, side-effects, expensive and partial lack of targeting specificity. So the design and synthesis of new molecules that perform specifically on target proteins in tumor cells is a focus of contemporary research. So many researchers aim for new drugs that will be more efficient, more selective, and less toxic. Because of the interesting structures and significant biological profile, naturally occurring acridines and xanthines as well as their analogues have attracted considerable interest in researchers and technologists. Natural and synthetic acridine derivatives form a significant category of heterocycles having nitrogen that is of considerable interest for organic chemists and biological communities due to their attractive anti-cancer activity. Another important class of therapeutic agents with diverse biological properties including cytotoxic effects is xanthine derivatives which are collectively called xanthines (a group of alkaloids). Among many significant molecules based on the structure of the purine, there is a group of natural xanthines, involving theobromine, caffeine, and theophylline and analogues of xanthine display anti-cancer activity. Hence the present chapter wishes to concentrate the attention on the synthesis and anti-cancer activity of acridine and xanthine-based compounds brilliantly.

Fast Mek1 Hit Identification with TRIC Technology Correlates Well with Other Biophysical Methods

2021 ◽  
pp. 247255522110262
Author(s):  
Semir Jeridi ◽  
Alexey Rak ◽  
Amit Gupta ◽  
Pierre Soule
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Rational Design ◽  
Weak Interactions ◽  
Chemical Space ◽  
Intensity Variation ◽  
Building Blocks ◽  
Intensity Change ◽  
Drug Candidates ◽  
Ideal Tool

The variety and complexity of drug targets are expanding rapidly. At the same time, there is significant interest in exploring a larger chemical space to identify new candidates. Fragment-based screening (FBS) has emerged as a popular alternative to traditional high-throughput screening campaigns to identify such drug candidates. FBS identifies hit fragments that exhibit weak interactions with the target of interest, thereby enabling the rational design of small-molecule compounds from the identified hit fragments, which serve as building blocks. This strategy reduces the number of molecules to screen while also allowing the exploration of a greater chemical space. Here we use temperature-related intensity change (TRIC) technology to perform FBS against the target MAPK/ERK kinase-1 (Mek1). TRIC describes the change in fluorescence intensity of a fluorescently labeled molecule upon a change in temperature. This intensity variation is dependent on the physicochemical environment in the vicinity of the dye and strongly affected by binding events. Thus, the detection of binding events is independent of mass, making TRIC an ideal tool for FBS. Using only 150 pmol of labeled Mek1, the authors screened 193 fragments from a prescreened library in less than 1 h of measurement time, leading to 66 hits. Among those hits, they identified more than 80% of the published top hits found using orthogonal techniques. Furthermore, TRIC allowed the identification of fragments that were of poor solubility but could be mistaken as false-positive hits in other methods.

scholarly journals The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5780
Author(s):  
Sergei Boichuk ◽  
Aigul Galembikova ◽  
Kirill Syuzov ◽  
Pavel Dunaev ◽  
Firuza Bikinieva ◽  
...  
Keyword(s):  
Binding Site ◽  
Cell Cycle Progression ◽  
Tubulin Polymerization ◽  
The Novel ◽  
Epithelial Cancer ◽  
Microtubule Network ◽  
Cycle Progression ◽  
Colchicine Binding Site ◽  
Anti Cancer

Microtubule targeting agents (MTAs) that interfere with the dynamic state of the mitotic spindle are well-known and effective chemotherapeutic agents. These agents interrupt the microtubule network via polymerization or depolymerization, halting the cell cycle progression and leading to apoptosis. We report two novel pyrrole-based carboxamides (CAs) (CA-61 and -84) as the compounds exhibiting potent anti-cancer properties against a broad spectrum of epithelial cancer cell lines, including breast, lung, and prostate cancer. The anti-cancer activity of CAs is due to their ability to interfere with the microtubules network and inhibit tubulin polymerization. Molecular docking demonstrated an efficient binding between these ligands and the colchicine-binding site on the tubulin. CA-61 formed two hydrogen bond interactions with THR 179 (B) and THR 353 (B), whereas two hydrogen bonds with LYS 254 (B) and 1 with ASN 101 (A) were identified for CA-84. The binding energy for CA-84 and CA-61 was −9.910 kcal/mol and −9.390 kcal/mol. A tubulin polymerization assay revealed a strong inhibition of tubulin polymerization induced by CA-61 and -84. The immunofluorescence data revealed the disruption of the tubulin assembly in CA-treated cancer cells. As an outcome of the tubulin inhibition, these compounds halted the cell cycle progression in the G2/M phase, leading to the accumulation of the mitotic cells, and further induced apoptosis. Lastly, the in vivo study indicated that CAs significantly inhibited the HCC1806 breast cancer xenograft tumor growth in a nude mouse model. Collectively, we identified the novel CAs as potent MTAs, inhibiting tubulin polymerization via binding to the colchicine-binding site, disrupting the microtubule network, and exhibiting potent pro-apoptotic activities against the epithelial cancer cell lines both in vitro and in vivo.

Prospective Anti-cancer Agents: A Recent Update on Drug Repurposing

2020 ◽  
Vol 20 ◽  
Author(s):  
Anjali S. Sabale ◽  
Unnati M. Patel ◽  
Ankita A. Gorhe ◽  
Vinayak R. Bodhankar ◽  
Mahesh N. Shinde ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput Screening ◽  
Target Identification ◽  
Clinical Status ◽  
Drug Repurposing ◽  
Research Strategy ◽  
Large Numbers ◽  
Anti Cancer ◽  
The Cost ◽  
New Anticancer Drugs

Background: The drug discovery phases traditionally involve target identification as well as lead optimization through high throughput screening, which is usually time-consuming with a higher risk failure. In the case of new anticancer drugs, drug accessibility remains a great challenge due to high pricing which usually leads to a huge economic burden on a cancer patient. Objective and Methods: Drug repurposing appears to be a better alternative method for drug development. Repurposing with many benefits as faster, cheaper, safer, and easier has become the most sought research strategy nowadays. Large numbers of approved drug are now being studied for cancer. In present review, we furnish recent updates on the field of repurposing especially about prospective anti-cancer agents including selected examples of potent phytochemicals from various authentic databases. Results: We have also detailed the current approaches utilized for repurposing along with the clinical status of the repurposed drug. Conclusion: Drug repurposing has potential and scope for reducing the cost of drug discovery in the oncology field.

scholarly journals Fumitremorgins and Relatives – From Tremorgenic Compounds to Valuable Anti-Cancer Drugs

2018 ◽  
Vol 25 (2) ◽  
pp. 123-140 ◽  
Author(s):  
Wolf-Rainer Abraham
Keyword(s):  
Cancer Cells ◽  
High Throughput Screening ◽  
Natural Compounds ◽  
Screening Methods ◽  
Cancer Therapies ◽  
Highly Active ◽  
Structure Activity ◽  
Anti Cancer ◽  
Derivatives Of ◽  
Related Compounds

Background: Fumitremorgins are mycotoxins but can also inhibit cancer cells and reverse their drug resistance. Objective: The bioactivity of prenylated cyclo-Trp-Pro dipeptides and their derivatives concerning their application in anti-cancer therapies will be discussed. Methods: Reports on the discovery and assessment of this class of fungal compounds are compiled from literature using Google Scholar and PubMed. The bioactivities of the natural compounds are discussed with the aim of their improvement for cancer therapy. Results: Although a number of compounds of this class have been found, only a minority of them showed bioactivity in the applied bioassays. Fumitremorgins and related compounds are active against various cancer cells but they are also mycotoxins. Some of these natural compounds can arrest cancer cells in their cell cycle and some can block ABC-transporters and reverse resistance in chemotherapy. Structure activity relationships have been deduced leading to the prediction of highly active compounds. Several easily accessible derivatives of these natural products have been discovered being highly selective and non-toxic. Conclusion: Sophisticated screening methods, high throughput screening, metabolic engineering, and synthetic biology are novel and promising technologies for the search for highly active drugs. Rapid gene sequencing in combination with engineered biosynthetic pathways should contribute substantially to novel pharmaceutics.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

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