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 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).