Faculty, Staff and Student Publications

Publication Date

10-12-2023

Journal

ACS Medicinal Chemistry Letters Journal

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).

DOI

10.1021/acsmedchemlett.3c00305

PMID

37849534

PMCID

PMC10577891

PubMedCentral® Posted Date

9-22-2023

PubMedCentral® Full Text Version

Post-print

ml3c00305_0010.jpg (110 kB)
Graphical Abstract

Published Open-Access

yes

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