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).

Document Type

Article

Publication Date

9-2023

Notes/Citation Information

© 2023 American Chemical Societ

Digital Object Identifier (DOI)

https://doi.org/10.1021/acsmedchemlett.3c00305

Funding Information

This work was supported by NIH CA070907, CPRIT RP210088, WELCH F-1390 (K.N.D); NIH R00CA225633, University of Kentucky Center for Cancer and Metabolism, funded through the NIH/NIGMS COBRE program under grant number P20 GM121327 (H.G.); NIH R01GM106137, R01GM114237 (P.R); NIH CA251067 (J.M.K); R01GM108583, computing from XSEDE through allocation TG-CHE160044, UNT CASCaM (partially funded by the NSF Grant Nos. CHE1531468 and OAC-2117247) and UT- Dallas’ Cyberinfrastructure and Research Services (G.A.C.).

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