June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Development of small molecule inhibitors against the corneal neovascularization via MMP14
Author Affiliations & Notes
  • Kyuyeon Han
    Illinois Eye and Ear Infirmary, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
  • HYUN LEE
    Illinois Eye and Ear Infirmary, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
  • Dimitri T Azar
    Illinois Eye and Ear Infirmary, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
  • Footnotes
    Commercial Relationships   Kyuyeon Han, None; HYUN LEE, None; Dimitri Azar, None
  • Footnotes
    Support  NEI (R01EY010101), Eversight, P30 Core grant (P30 EY001792) and unrestricted grant support from the RPB
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 901. doi:
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      Kyuyeon Han, HYUN LEE, Dimitri T Azar; Development of small molecule inhibitors against the corneal neovascularization via MMP14. Invest. Ophthalmol. Vis. Sci. 2021;62(8):901.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To explore the potentiality of quinoline based small molecules for matrix metalloproteinase 14 (MMP14) inhibitors.

Methods : We optimized and established to identify specific and unique MMP14 inhibitors through two-stage assays. Primary high-throughput (HTS) by fluorescence-based enzymatic assay was performed to determine IC50 value. We determined dissociation equilibrium constant (KD) between cat-MMP14 with candidate compounds using surface plasmon resonance (SPR) to validate selected hit compounds. cat-MMP14 was immobilized on a CM5 sensor chip using the standard amine-coupling method using a Biacore 8K instrument. Compound solutions with a series of increasing concentrations (0 to 50 uM at 1.5-fold dilution) were applied to all channels at a 30 mL/min flow rate at 25 oC. The KD values were determined by fitting the data with either steady-state affinity or 1:1 Langmuir kinetic fitting. To investigate the potentiality to develop MMP14 inhibitors, we determined a structure-activity relationship (SAR) with twelve quinoline analogs using a fluorescence-based enzymatic assay.

Results : Three compounds (clioquinol, chloroxine, and folic acid) containing quinoline as a base structure showed inhibitory effects of MMP14. We found that two compounds (clioquinol and chloroxine) directly bound to act-MMP14 using SPR analysis. Clioquinol, chloroxine, and folic acid did not show cytotoxicity on corneal epithelial and fibroblast cells.

Conclusions : Our results show that quinoline containing small molecules inhibited MMP14 enzymatic activity. Based on these findings, we propose that the unique MMP14 inhibitors can specifically inactivate the MMP14 enzyme activity, leading to inhibition of corneal neovascularization via MMP14.

This is a 2021 ARVO Annual Meeting abstract.

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