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

doi:10.1021/acsmedchemlett.3c00305

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

ACS Med Chem Lett. 2023 Sep 22;14(10):1396-1403. doi: 10.1021/acsmedchemlett.3c00305. eCollection 2023 Oct 12.

Authors

Juhoon Lee^{1

2}, Hou-Fu Guo³, Shike Wang⁴, Yazdan Maghsoud⁵, Erik Antonio Vázquez-Montelongo⁶, Zhifeng Jing⁷, Rae M Sammons^{1

2}, Eun Jeong Cho^{1

2}, Pengyu Ren⁷, G Andrés Cisneros^{5

8}, Jonathan M Kurie⁴, Kevin N Dalby^{1

2}

Affiliations

¹ Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, United States.
² Targeted Therapeutic Drug Discovery and Development Program, College of Pharmacy, University of Texas, Austin, Texas 78712, United States.
³ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536, United States.
⁴ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
⁵ Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States.
⁶ Department of Physical Medicine and Rehabilitation, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
⁷ Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States.
⁸ Department of Physics, The University of Texas at Dallas, Richardson, Texas 75080, United States.

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).

Abstract

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