Year: 2023
Type: article
Abstract: Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1–18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 may stem from noncovalent interactions like hydrogen bonding between the morpholine/piperazine rings with the LH2-specific Arg661. Treatment of 344SQ WT cells with 13 resulted in a dose-dependent reduction in their migration potential, whereas the compound did not impede the migration of the same cell line with an LH2 knockout (LH2KO).
Source: ACS Medicinal Chemistry Letters
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: National Science Foundation, Welch Foundation, Cancer Prevention and Research Institute of Texas, University of Texas Southwestern Medical Center, University of Texas at Austin, University of Texas at Dallas, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of General Medical Sciences, Division of Chemistry
Awards: G1135378803, G1144718286, Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications, MRI: Acquisition of a High Performance Hybrid Computer Cluster for Computational Modeling, G3252379793, G3667714879, G4950536974, G52711424, G5363805725, G5748168713, G6375272071, G7077335631, G7186293888, G7324978312, Targeted Therapeutic Drug Discovery & Development Program, G7678928379, G8041988672, G9000112290, G9000217152, G9000230098, Elucidating pro-metastatic collagen modifying activities of lysyl hydroxylase 2, University of Kentucky Center for Cancer Metabolism, G904012196, G995644284
OpenAlex ID: W4386951268