scholarly journals Unravelling the Allosteric Targeting of PHGDH at the ACT-Binding Domain with a Photoactivatable Diazirine Probe and Mass Spectrometry Experiments

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 477
Author(s):  
Quentin Spillier ◽  
Séverine Ravez ◽  
Simon Dochain ◽  
Didier Vertommen ◽  
Léopold Thabault ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Anticancer Drugs ◽  
Mechanism Of Action ◽  
Rational Design ◽  
Biosynthetic Pathway ◽  
Allosteric Site ◽  
Site Of Action ◽  
Phosphoglycerate Dehydrogenase ◽  
New Anticancer Drugs

The serine biosynthetic pathway is a key element contributing to tumor proliferation. In recent years, targeting of phosphoglycerate dehydrogenase (PHGDH), the first enzyme of this pathway, intensified and revealed to be a promising strategy to develop new anticancer drugs. Among attractive PHGDH inhibitors are the α-ketothioamides. In previous work, we have demonstrated their efficacy in the inhibition of PHGDH in vitro and in cellulo. However, the precise site of action of this series, which would help the rational design of new inhibitors, remained undefined. In the present study, the detailed mechanism-of-action of a representative α-ketothioamide inhibitor is reported using several complementary experimental techniques. Strikingly, our work led to the identification of an allosteric site on PHGDH that can be targeted for drug development. Using mass spectrometry experiments and an original α-ketothioamide diazirine-based photoaffinity probe, we identified the 523Q-533F sequence on the ACT regulatory domain of PHGDH as the binding site of α-ketothioamides. Mutagenesis experiments further documented the specificity of our compound at this allosteric site. Our results thus pave the way for the development of new anticancer drugs using a completely novel mechanism-of-action.

scholarly journals How Computational Chemistry and Drug Delivery Techniques Can Support the Development of New Anticancer Drugs

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1756 ◽  
Author(s):  
Mariangela Garofalo ◽  
Giovanni Grazioso ◽  
Andrea Cavalli ◽  
Jacopo Sgrignani
Keyword(s):  
Drug Delivery ◽  
Anticancer Drugs ◽  
Rational Design ◽  
Significant Contribution ◽  
Research Experience ◽  
Computer Aided Drug Design ◽  
Target Drug Delivery ◽  
Research Fields ◽  
Target Drug ◽  
New Anticancer Drugs

The early and late development of new anticancer drugs, small molecules or peptides can be slowed down by some issues such as poor selectivity for the target or poor ADME properties. Computer-aided drug design (CADD) and target drug delivery (TDD) techniques, although apparently far from each other, are two research fields that can give a significant contribution to overcome these problems. Their combination may provide mechanistic understanding resulting in a synergy that makes possible the rational design of novel anticancer based therapies. Herein, we aim to discuss selected applications, some also from our research experience, in the fields of anticancer small organic drugs and peptides.

scholarly journals A multilayered cancer-on-a-chip model to analyze the effectiveness of new-generation photosensitizers

The Analyst ◽  
2020 ◽  
Vol 145 (21) ◽  
pp. 6937-6947
Author(s):  
Magdalena Flont ◽  
Elżbieta Jastrzębska ◽  
Zbigniew Brzózka
Keyword(s):  
Anticancer Drugs ◽  
Three Dimensional ◽  
Cancer Tissue ◽  
Cellular Models ◽  
New Generation ◽  
New Anticancer Drugs

Three-dimensional (3D) cellular models of cancer tissue are necessary tools to analyze new anticancer drugs under in vitro conditions.

The discovery and structural requirements of inhibitors of p-hydroxyphenylpyruvate dioxygenase

Weed Science ◽  
1997 ◽  
Vol 45 (5) ◽  
pp. 601-609 ◽  
Author(s):  
David L. Lee ◽  
Michael P. Prisbylla ◽  
Thomas H. Cromartie ◽  
Derek P. Dagarin ◽  
Stott W. Howard ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Biosynthetic Pathway ◽  
Carotenoid Biosynthesis ◽  
Phytoene Desaturase ◽  
Rat Urine ◽  
Meristematic Tissue ◽  
Chemically Induced ◽  
Mammalian Enzyme ◽  
Unique Mechanism

The benzoylcyclohexane-1,3-diones, the triketones, are potent bleaching herbicides whose structure-activity relationships and physical properties are substantially different from classical bleaching herbicides, which affect phytoene desaturase. The first clue to their unique mechanism of action was the discovery that rats treated with a triketone were found to be tyrosinemic. Additionally, examination of the rat urine revealed the accumulation of p-hydroxyphenylpyruvate (HPP) and p-hydroxyphenyllactate. These results suggested that this chemically induced tyrosinemia was the result of the inhibition of p-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27), and this suggestion was confirmed when a triketone was shown to be a potent inhibitor of rat liver HPPD. In plants, HPPD is a component of the biosynthetic pathway to plastoquinone (PQ), which in turn is a key cofactor of phytoene desaturase. The expectation that triketone-treated plants should accumulate tyrosine while having reduced PQ levels was dramatically demonstrated in the meristematic tissue of ivyleaf morningglory. Plant HPPD, like the mammalian enzyme, was inhibited in vitro by triketones. These biochemical effects provide evidence that the triketone herbicidal mechanism of action is HPPD inhibition leading to a deficiency of PQ, a key cofactor for carotenoid biosynthesis. Other chemical classes of bleaching herbicides were also examined for their ability to elevate tyrosine and deplete PQ as a definitive means of establishing their mode of action and for delineating the structural and physical chemical requirements for an HPPD herbicide. Evidence is provided to support the claim that a 2-benzoylethen-1-ol substructure is the minimum substructure required for a potent HPPD inhibitor.

scholarly journals Elucidation of the Mechanism of Action for Metal Based Anticancer Drugs by Mass Spectrometry-Based Quantitative Proteomics

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 581 ◽  
Author(s):  
Shuailong Jia ◽  
Runjing Wang ◽  
Kui Wu ◽  
Hongliang Jiang ◽  
Zhifeng Du
Keyword(s):  
Mass Spectrometry ◽  
Anticancer Drugs ◽  
Mechanism Of Action ◽  
Quantitative Proteomics ◽  
High Sensitivity ◽  
Mass Spectrometric ◽  
Protein Adducts ◽  
Ionization Mass ◽  
Soft Ionization ◽  
Binding Partners

The discovery of the anticancer activity of cisplatin and its clinical application has opened a new field for studying metal-coordinated anticancer drugs. Metal-based anticancer drugs, such as cisplatin, can be transported to cells after entering into the human body and form metal–DNA or metal–protein adducts. Then, responding proteins will recognize adducts and form stable complexes. The proteins that were binding with metal-based anticancer drugs were relevant to their mechanism of action. Herein, investigation of the recognition between metal-based anticancer drugs and its binding partners will further our understanding about the pharmacology of cytotoxic anticancer drugs and help optimize the structure of anticancer drugs. The “soft” ionization mass spectrometric methods have many advantages such as high sensitivity and low sample consumption, which are suitable for the analyses of complex biological samples. Thus, MS has become a powerful tool for the identification of proteins binding or responding to metal-based anticancer drugs. In this review, we focused on the mass spectrometry-based quantitative strategy for the identification of proteins specifically responding or binding to metal-based anticancer drugs, ultimately elucidating their mechanism of action.

scholarly journals Bioactive Olivacine Derivatives—Potential Application in Cancer Therapy

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 564
Author(s):  
Beata Tylińska ◽  
Benita Wiatrak
Keyword(s):  
Clinical Trials ◽  
Biological Activity ◽  
Growth Factors ◽  
Anticancer Drugs ◽  
Inhibition Of Growth ◽  
Structure Activity ◽  
Sar Analysis ◽  
New Anticancer Drugs

 Olivacine and its derivatives are characterized by multidirectional biological activity. Noteworthy is their antiproliferative effect related to various mechanisms, such as inhibition of growth factors, enzymes, kinases and others. The activity of these compounds was tested on cell lines of various tumors. In most publications, the most active olivacine derivatives exceeded the effects of doxorubicin (a commonly used anticancer drug), so in the future, they may become the main new anticancer drugs. In this publication, we present the groups of the most active olivacine derivatives obtained. In this work, the in vitro and in vivo activity of olivacine and its most active derivatives are presented. We describe olivacine derivatives that have been in clinical trials. We conducted a structure–activity relationship (SAR) analysis that may be used to obtain new olivacine derivatives with better properties than the available anticancer drugs. 

scholarly journals Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads

2014 ◽  
Vol 31 (9) ◽  
pp. 1202-1226 ◽  
Author(s):  
Qiao-Hong Chen ◽  
David G. I. Kingston
Keyword(s):  
Anticancer Drugs ◽  
Mechanism Of Action ◽  
Potential Mechanism ◽  
New Anticancer Drugs

Zampanolide and its structural relative dactylolide are promising new tubulin-assembly agents with the potential to become new anticancer drugs. This review covers their sources and isolation, structures, anticancer potential, mechanism of action, and syntheses.

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