scholarly journals Progress Towards a Public Chemogenomic Set for Protein Kinases and a Call for Contributions

2017 ◽  
Author(s):  
David H. Drewry ◽  
Carrow I. Wells ◽  
David M. Andrews ◽  
Richard Angell ◽  
Hassan Al-Ali ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Kinases ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Biological Function ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Human Protein ◽  
Catalytic Function ◽  
Full Complement

AbstractProtein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.

scholarly journals Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

2020 ◽  
Vol 21 (20) ◽  
pp. 7549
Author(s):  
Paula Martín Moyano ◽  
Václav Němec ◽  
Kamil Paruch
Keyword(s):  
Clinical Trials ◽  
Protein Kinases ◽  
Small Molecule ◽  
Chemical Biology ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Chemical Probes ◽  
The Family

Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes.

scholarly journals The selectivity of protein kinase inhibitors: a further update

2007 ◽  
Vol 408 (3) ◽  
pp. 297-315 ◽  
Author(s):  
Jenny Bain ◽  
Lorna Plater ◽  
Matt Elliott ◽  
Natalia Shpiro ◽  
C. James Hastie ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Specific Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Casein Kinase 1

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)–raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

2020 ◽  
Author(s):  
Chao Wang ◽  
Juan Diez ◽  
Hajeung Park ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Hydroxamic Acid ◽  
Therapeutic Potential ◽  
Preceding Paper ◽  
Close Relative ◽  
Specific Inhibition ◽  
Selective Inhibitors

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

Determination of Amino Acid Residues Responsible for Specific Interaction of Protein Kinases with Small Molecule Inhibitors

2018 ◽  
Vol 52 (3) ◽  
pp. 478-487 ◽  
Author(s):  
D. A. Karasev ◽  
A. V. Veselovsky ◽  
A. A. Lagunin ◽  
D. A. Filimonov ◽  
B. N. Sobolev
Keyword(s):  
Amino Acid ◽  
Protein Kinases ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Specific Interaction ◽  
Amino Acid Residues

scholarly journals A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency

2020 ◽  
Vol 117 (40) ◽  
pp. 24802-24812 ◽  
Author(s):  
Salima Daou ◽  
Manisha Talukdar ◽  
Jinle Tang ◽  
Beihua Dong ◽  
Shuvojit Banerjee ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Protein Kinase Inhibitors ◽  
Response To Treatment ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
In Cells

The oligoadenylate synthetase (OAS)–RNase L system is an IFN-inducible antiviral pathway activated by viral infection. Viral double-stranded (ds) RNA activates OAS isoforms that synthesize the second messenger 2-5A, which binds and activates the pseudokinase-endoribonuclease RNase L. In cells, OAS activation is tamped down by ADAR1, an adenosine deaminase that destabilizes dsRNA. Mutation of ADAR1 is one cause of Aicardi-Goutières syndrome (AGS), an interferonopathy in children. ADAR1 deficiency in human cells can lead to RNase L activation and subsequent cell death. To evaluate RNase L as a possible therapeutic target for AGS, we sought to identify small-molecule inhibitors of RNase L. A 500-compound library of protein kinase inhibitors was screened for modulators of RNase L activity in vitro. We identified ellagic acid (EA) as a hit with 10-fold higher selectivity against RNase L compared with its nearest paralog, IRE1. SAR analysis identified valoneic acid dilactone (VAL) as a superior inhibitor of RNase L, with 100-fold selectivity over IRE1. Mechanism-of-action analysis indicated that EA and VAL do not bind to the pseudokinase domain of RNase L despite acting as ATP competitive inhibitors of the protein kinase CK2. VAL is nontoxic and functional in cells, although with a 1,000-fold decrease in potency, as measured by RNA cleavage activity in response to treatment with dsRNA activator or by rescue of cell lethality resulting from self dsRNA induced by ADAR1 deficiency. These studies lay the foundation for understanding novel modes of regulating RNase L function using small-molecule inhibitors and avenues of therapeutic potential.

Novel Small-Molecule Inhibitors of Arylamine N-Acetyltransferases: Drug Discovery by High Throughput Screening

2011 ◽  
Vol 14 (2) ◽  
pp. 117-124 ◽  
Author(s):  
Isaac M. Westwood ◽  
Akane Kawamura ◽  
Angela J. Russell ◽  
James Sandy ◽  
Stephen G. Davies ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors

scholarly journals A Central Role for Biophysics in Cancer Drug Discovery - Development of Candidate Small Molecule Inhibitors in Mutant KRas

2018 ◽  
Vol 114 (3) ◽  
pp. 30a-31a ◽  
Author(s):  
Andrea Gohlke ◽  
Justin Bower ◽  
Peter N. Brown ◽  
Ken S. Cameron ◽  
Martin Drysdale ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cancer Drug ◽  
Cancer Drug Discovery

Small Molecule Inhibitors of Protein Kinases in Cancer- How to Overcome Resistance

2006 ◽  
Vol 6 (10) ◽  
pp. 1101-1110 ◽  
Author(s):  
R. Griffith ◽  
M. N. Brown ◽  
A. McCluskey ◽  
L. K. Ashman
Keyword(s):  
Protein Kinases ◽  
Small Molecule ◽  
Small Molecule Inhibitors

scholarly journals Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

2016 ◽  
Vol 18 (4) ◽  
pp. 898-913 ◽  
Author(s):  
Zhiwei Feng ◽  
Larry V. Pearce ◽  
Yu Zhang ◽  
Changrui Xing ◽  
Brienna K. A. Herold ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential
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