scholarly journals Targeting phospholipase D with small-molecule inhibitors as a potential therapeutic approach for cancer metastasis

2009 ◽  
Vol 5 (9) ◽  
pp. 1477-1486 ◽  
Author(s):  
Wenjuan Su ◽  
Qin Chen ◽  
Michael A Frohman
Keyword(s):  
Small Molecule ◽  
Phospholipase D ◽  
Therapeutic Approach ◽  
Cancer Metastasis ◽  
Small Molecule Inhibitors

scholarly journals Development of a High-Throughput Lysyl Hydroxylase (LH) Assay and Identification of Small-Molecule Inhibitors against LH2

2018 ◽  
Vol 24 (4) ◽  
pp. 484-491 ◽  
Author(s):  
Ashwini K. Devkota ◽  
John R. Veloria ◽  
Hou-Fu Guo ◽  
Jonathan M. Kurie ◽  
Eun Jeong Cho ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cancer Metastasis ◽  
Small Molecule Inhibitors ◽  
Lysyl Hydroxylase ◽  
Promising Target ◽  
Lysine Residues ◽  
Collagen Molecules ◽  
Cross Links

Lysyl hydroxylase-2 (LH2) catalyzes the hydroxylation of telopeptidyl lysine residues on collagen, leading to the formation of stable collagen cross-links that connect collagen molecules and stabilize the extracellular matrix. High levels of LH2 have been reported in the formation and stabilization of hydroxylysine aldehyde-derived collagen cross-links (HLCCs), leading to fibrosis and cancer metastasis in certain tissues. Identification of small-molecule inhibitors targeting LH2 activity requires a robust and suitable assay system, which is currently lacking. Thus, despite being a promising target for these diseases, small-molecule inhibitors for LH2 have yet to be reported. Therefore, we developed a luminescence-based strategy to monitor LH activity and validated its ability to identify new inhibitors in a screen of approximately 65,000 compounds against LH2. Primary hits were confirmed using the same LH assay against mimiviral L230. This newly developed LH assay is robust, suitable for high-throughput screening, and able to identify potent specific inhibitors of LH2.

scholarly journals KRAS is vulnerable to reversible switch-II pocket engagement in cells

2021 ◽  
Author(s):  
James D Vasta ◽  
D. Matthew Peacock ◽  
Qinheng Zheng ◽  
Joel A Walker ◽  
Ziyang Zhang ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Binding Site ◽  
Small Molecule ◽  
Therapeutic Approach ◽  
Small Molecule Inhibitors ◽  
Drug Binding ◽  
Gtp Hydrolysis ◽  
Drug Binding Site ◽  
Covalent Ligands ◽  
P Ligands

Current small molecule inhibitors of KRAS (G12C) bind irreversibly in the switch-II pocket, exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the switch-II pocket is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a novel cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the switch-II pockets of many GTP hydrolysis-deficient KRAS hotspot (G12, G13, Q61) mutants are accessible using non-covalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the switch-II pocket as a privileged drug binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.

scholarly journals Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies

2015 ◽  
Vol 12 (9) ◽  
pp. 814-828 ◽  
Author(s):  
Marcus Pickhardt ◽  
Thomas Neumann ◽  
Daniel Schwizer ◽  
Kari Callaway ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Approach ◽  
Small Molecule Inhibitors ◽  
Tau Aggregation

scholarly journals Targeting Loxosceles spider Sphingomyelinase D with small-molecule inhibitors as a potential therapeutic approach for loxoscelism

2019 ◽  
Vol 34 (1) ◽  
pp. 310-321 ◽  
Author(s):  
Priscila Hess Lopes ◽  
Mário T. Murakami ◽  
Fernanda C. V. Portaro ◽  
Kerly Fernanda Mesquita Pasqualoto ◽  
Carmen van den Berg ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Approach ◽  
Small Molecule Inhibitors
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