Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors.

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 and from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, -, and identified and that inhibit LH2 with IC's of approximately 300 and 500 nM, respectively. Compounds and demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of and may stem from noncovalent interactions like hydrogen bonding between the morpholine/piperazine rings with the LH2-specific Arg661. Treatment of 344SQ WT cells with 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).