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

Juhoon Lee, Hou Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M. Sammons, Eun Jeong Cho, Pengyu Ren, G. Andrés Cisneros, Jonathan M. Kurie, Kevin N. Dalby

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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).

Original languageEnglish
Pages (from-to)1396-1403
Number of pages8
JournalACS Medicinal Chemistry Letters
Issue number10
StatePublished - Oct 12 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.


  • Collagen
  • HLCC
  • Hydroxylysine aldehyde-derived collagen cross-links
  • Inhibitor
  • LH2
  • Lysyl hydroxylase 2
  • α-Ketoglutarate

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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