Chemical Space Exploration of Oxetanes

This paper focuses on new derivatives bearing an oxetane group to extend accessible chemical space for further identification of kinase inhibitors. The ability to modulate kinase activity represents an important therapeutic strategy for the treatment of human illnesses. Known as a nonclassical isoster of the carbonyl group, due to its high polarity and great ability to function as an acceptor of hydrogen bond, oxetane seems to be an attractive and underexplored structural motif in medicinal chemistry.

Download Full-text

Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity

NeuroMolecular Medicine ◽

10.1007/s12017-019-08577-z ◽

2019 ◽

Vol 22 (2) ◽

pp. 218-226 ◽

Cited By ~ 3

Author(s):

Joan Poh Ling Sim ◽

Wang Ziyin ◽

Adeline Henry Basil ◽

Shuping Lin ◽

Zhongcan Chen ◽

...

Keyword(s):

Protein Phosphorylation ◽

Therapeutic Strategy ◽

Kinase Activity ◽

Kinase Inhibitors ◽

Leucine Rich Repeat ◽

Disease Phenotype ◽

S6 Kinase ◽

Ribosomal S6 Kinase

Abstract Mutations in LRRK2 are currently recognized as the most common monogenetic cause of Parkinsonism. The elevation of kinase activity of LRRK2 that frequently accompanies its mutations is widely thought to contribute to its toxicity. Accordingly, many groups have developed LRRK2-specific kinase inhibitors as a potential therapeutic strategy. Given that protein phosphorylation is a reversible event, we sought to elucidate the phosphatase(s) that can reverse LRRK2-mediated phosphorylation, with the view that targeting this phosphatase(s) may similarly be beneficial. Using an unbiased RNAi phosphatase screen conducted in a Drosophila LRRK2 model, we identified PP2A as a genetic modulator of LRRK2-induced neurotoxicity. Further, we also identified ribosomal S6 kinase (S6K), a target of PP2A, as a novel regulator of LRRK2 function. Finally, we showed that modulation of PP2A or S6K activities ameliorates LRRK2-associated disease phenotype in Drosophila.

Download Full-text

Chemical space exploration based on recurrent neural networks: applications in discovering kinase inhibitors

Journal of Cheminformatics ◽

10.1186/s13321-020-00446-3 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Xuanyi Li ◽

Yinqiu Xu ◽

Hequan Yao ◽

Kejiang Lin

Keyword(s):

Neural Networks ◽

Recurrent Neural Networks ◽

Kinase Inhibitors ◽

Chemical Space ◽

Space Exploration

Download Full-text

Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055

Biochemical Society Transactions ◽

10.1042/bst0390456 ◽

2011 ◽

Vol 39 (2) ◽

pp. 456-459 ◽

Cited By ~ 24

Author(s):

Gayle Marshall ◽

Zoe Howard ◽

Jonathan Dry ◽

Sarah Fenton ◽

Dan Heathcote ◽

...

Keyword(s):

Therapeutic Strategy ◽

Kinase Activity ◽

Clinical Evidence ◽

Kinase Inhibitors ◽

Biological Effects ◽

Mammalian Target Of Rapamycin ◽

Allosteric Inhibitors ◽

Phenotypic Differences ◽

Mtor Kinase ◽

Molecule Inhibitor

AZD8055 is a small-molecule inhibitor of mTOR (mammalian target of rapamycin) kinase activity. The present review highlights molecular and phenotypic differences between AZD8055 and allosteric inhibitors of mTOR such as rapamycin. Biomarkers, some of which are applicable to clinical studies, as well as biological effects such as autophagy, growth inhibition and cell death are compared between AZD8055 and rapamycin. Potential ways to develop rational combinations with mTOR kinase inhibitors are also discussed. Overall, AZD8055 may provide a better therapeutic strategy than rapamycin and analogues.

Download Full-text

Novel Chemical Class of pUL97 Protein Kinase-Specific Inhibitors with Strong Anticytomegaloviral Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.11.4154-4162.2004 ◽

2004 ◽

Vol 48 (11) ◽

pp. 4154-4162 ◽

Cited By ~ 98

Author(s):

Thomas Herget ◽

Martina Freitag ◽

Monika Morbitzer ◽

Regina Kupfer ◽

Thomas Stamminger ◽

...

Keyword(s):

Protein Kinase ◽

Kinase Activity ◽

Kinase Inhibitors ◽

High Efficiency ◽

Fluorescent Protein ◽

Human Fibroblasts ◽

Growth Factor Receptor ◽

Protein Kinase Activity ◽

Hcmv Replication

ABSTRACT Human cytomegalovirus (HCMV) is a major human pathogen frequently associated with life-threatening disease in immunosuppressed patients and newborns. The HCMV UL97-encoded protein kinase (pUL97) represents an important determinant of viral replication. Recent studies demonstrated that pUL97-specific kinase inhibitors are powerful tools for the control of HCMV replication. We present evidence that three related quinazoline compounds are potent inhibitors of the pUL97 kinase activity and block in vitro substrate phosphorylation, with 50% inhibitory concentrations (IC50s) between 30 and 170 nM. Replication of HCMV in primary human fibroblasts was suppressed with a high efficiency. The IC50s of these three quinazoline compounds (2.4 ± 0.4, 3.4 ± 0.6, and 3.9 ± 1.1 μM, respectively) were in the range of the IC50 of ganciclovir (1.2 ± 0.2 μM), as determined by the HCMV green fluorescent protein-based antiviral assay. Importantly, the quinazolines were demonstrated to have strong inhibitory effects against clinical HCMV isolates, including ganciclovir- and cidofovir-resistant virus variants. Moreover, in contrast to ganciclovir, the formation of resistance to the quinazolines was not observed. The mechanisms of action of these compounds were confirmed by kinetic analyses with infected cells. Quinazolines specifically inhibited viral early-late protein synthesis but had no effects at other stages of the replication cycle, such as viral entry, consistent with a blockage of the pUL97 function. In contrast to epithelial growth factor receptor inhibitors, quinazolines affected HCMV replication even when they were added hours after virus adsorption. Thus, our findings indicate that quinazolines are highly efficient inhibitors of HCMV replication in vitro by targeting pUL97 protein kinase activity.

Download Full-text

Phosphoinositides Regulate Membrane-dependent Actin Assembly by Latex Bead Phagosomes

Molecular Biology of the Cell ◽

10.1091/mbc.01-06-0314 ◽

2002 ◽

Vol 13 (4) ◽

pp. 1190-1202 ◽

Cited By ~ 51

Author(s):

Hélène Defacque ◽

Evelyne Bos ◽

Boyan Garvalov ◽

Cécile Barret ◽

Christian Roy ◽

...

Keyword(s):

Binding Sites ◽

Kinase Activity ◽

Kinase Inhibitors ◽

Membrane Surface ◽

Latex Bead ◽

Actin Assembly ◽

Wild Type ◽

Membrane Surfaces ◽

Organelle Membrane

Actin assembly on membrane surfaces is an elusive process in which several phosphoinositides (PIPs) have been implicated. We have reconstituted actin assembly using a defined membrane surface, the latex bead phagosome (LBP), and shown that the PI(4,5)P2-binding proteins ezrin and/or moesin were essential for this process ( Defacque et al., 2000b ). Here, we provide several lines of evidence that both preexisting and newly synthesized PI(4,5)P2, and probably PI(4)P, are essential for phagosomal actin assembly; only these PIPs were routinely synthesized from ATP during in vitro actin assembly. Treatment of LBP with phospholipase C or with adenosine, an inhibitor of type II PI 4-kinase, as well as preincubation with anti-PI(4)P or anti-PI(4,5)P2 antibodies all inhibited this process. Incorporation of extra PI(4)P or PI(4,5)P2 into the LBP membrane led to a fivefold increase in the number of phagosomes that assemble actin. An ezrin mutant mutated in the PI(4,5)P2-binding sites was less efficient in binding to LBPs and in reconstituting actin assembly than wild-type ezrin. Our data show that PI 4- and PI 5-kinase, and under some conditions also PI 3-kinase, activities are present on LBPs and can be activated by ATP, even in the absence of GTP or cytosolic components. However, PI 3-kinase activity is not required for actin assembly, because the process was not affected by PI 3-kinase inhibitors. We suggest that the ezrin-dependent actin assembly on the LBP membrane may require active turnover of D4 and D5 PIPs on the organelle membrane.

Download Full-text

Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer’s Disease: A Computational Study

Marine Drugs ◽

10.3390/md16100386 ◽

2018 ◽

Vol 16 (10) ◽

pp. 386 ◽

Cited By ~ 10

Author(s):

Laura Llorach-Pares ◽

Alfons Nonell-Canals ◽

Conxita Avila ◽

Melchor Sanchez-Martinez

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Strategy ◽

Kinase Inhibitors ◽

Computational Study ◽

Therapeutic Application ◽

Ongoing Research ◽

Casein Kinase 1 ◽

Dual Specificity ◽

Potential Therapeutic Application

Alzheimer’s disease (AD) is becoming one of the most disturbing health and socioeconomic problems nowadays, as it is a neurodegenerative pathology with no treatment, which is expected to grow further due to population ageing. Actual treatments for AD produce only a modest amelioration of symptoms, although there is a constant ongoing research of new therapeutic strategies oriented to improve the amelioration of the symptoms, and even to completely cure the disease. A principal feature of AD is the presence of neurofibrillary tangles (NFT) induced by the aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Glycogen synthetase kinase-3 beta (GSK3β), casein kinase 1 delta (CK1δ), dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and dual-specificity kinase cdc2-like kinase 1 (CLK1) have been identified as the principal proteins involved in this process. Due to this, the inhibition of these kinases has been proposed as a plausible therapeutic strategy to fight AD. In this study, we tested in silico the inhibitory activity of different marine natural compounds, as well as newly-designed molecules from some of them, over the mentioned protein kinases, finding some new possible inhibitors with potential therapeutic application.

Download Full-text

Autoregulatory control of microtubule binding in doublecortin-like kinase 1

eLife ◽

10.7554/elife.60126 ◽

2021 ◽

Vol 10 ◽

Author(s):

Regina L Agulto ◽

Melissa M Rogers ◽

Tracy C Tan ◽

Amrita Ramkumar ◽

Ashlyn M Downing ◽

...

Keyword(s):

Binding Affinity ◽

Therapeutic Target ◽

Kinase Activity ◽

Kinase Inhibitors ◽

Binding Domain ◽

Cancer Development ◽

Microtubule Binding ◽

Microtubule Binding Domain

The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 have diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.

Download Full-text

ChemSpaX: Exploration of Chemical Space by Automated Functionalization of Molecular Scaffold

10.26434/chemrxiv.14617320 ◽

2021 ◽

Author(s):

Adarsh Kalikadien ◽

Evgeny A. Pidko ◽

Vivek Sinha

Keyword(s):

Force Field ◽

High Throughput ◽

High Throughput Screening ◽

Chemical Space ◽

Space Exploration ◽

Molecular Structures ◽

Data Driven ◽

Pincer Complexes ◽

Cobalt Porphyrin ◽

Input Structure

<div>Local chemical space exploration of an experimentally synthesized material can be done by making slight structural</div><div>variations of the synthesized material. This generation of many molecular structures with reasonable quality,</div><div>that resemble an existing (chemical) purposeful material, is needed for high-throughput screening purposes in</div><div>material design. Large databases of geometry and chemical properties of transition metal complexes are not</div><div>readily available, although these complexes are widely used in homogeneous catalysis. A Python-based workflow,</div><div>ChemSpaX, that is aimed at automating local chemical space exploration for any type of molecule, is introduced.</div><div>The overall computational workflow of ChemSpaX is explained in more detail. ChemSpaX uses 3D information,</div><div>to place functional groups on an input structure. For example, the input structure can be a catalyst for which one</div><div>wants to use high-throughput screening to investigate if the catalytic activity can be improved. The newly placed</div><div>substituents are optimized using a computationally cheap force-field optimization method. After placement of</div><div>new substituents, higher level optimizations using xTB or DFT instead of force-field optimization are also possible</div><div>in the current workflow. In representative applications of ChemSpaX, it is shown that the structures generated by</div><div>ChemSpaX have a reasonable quality for usage in high-throughput screening applications. Representative applications</div><div>of ChemSpaX are shown by investigating various adducts on functionalized Mn-based pincer complexes,</div><div>hydrogenation of Ru-based pincer complexes, functionalization of cobalt porphyrin complexes and functionalization</div><div>of a bipyridyl functionalized cobalt-porphyrin trapped in a M2L4 type cage complex. Descriptors such as</div><div>the Gibbs free energy of reaction and HOMO-LUMO gap, that can be used in data-driven design and discovery</div><div>of catalysts, were selected and studied in more detail for the selected use cases. The relatively fast GFN2-xTB</div><div>method was used to calculate these descriptors and a comparison was done against DFT calculated descriptors.</div><div>ChemSpaX is open-source and aims to bolster the efforts of the scientific community towards data-driven material</div><div>discovery.</div>

Download Full-text

Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2016265118 ◽

2021 ◽

Vol 118 (10) ◽

pp. e2016265118

Author(s):

Mahmoud S. Ahmed ◽

Ping Wang ◽

Ngoc Uyen Nhi Nguyen ◽

Yuji Nakada ◽

Ivan Menendez-Montes ◽

...

Keyword(s):

Neuropathic Pain ◽

Tyrosine Kinase ◽

Kinase Activity ◽

Kinase Inhibitors ◽

Catalytic Domain ◽

Therapeutic Option ◽

Atp Binding ◽

Approved Drugs ◽

Fda Approved Drugs

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

Download Full-text