2. Academic Validation
  3. Pyrazolines inhibiting the activity of the early growth response-1 DNA-binding domain

Pyrazolines inhibiting the activity of the early growth response-1 DNA-binding domain

  • Bioorg Med Chem Lett. 2024 Sep 10:113:129952. doi: 10.1016/j.bmcl.2024.129952.
Hyuk Yoon 1,  Dongsoo Koh 2,  Yoongho Lim 3,  Young Han Lee 4,  Jung Kul Lee 1,  Soon Young Shin 5
Affiliations

Affiliations

  • 1 Division of Chemical Engineering, Konkuk University, Seoul 05029, Republic of Korea.
  • 2 Department of Applied Chemistry, Dongduk Women's University, Seoul 02748, Republic of Korea.
  • 3 Division of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
  • 4 Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea.
  • 5 Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea. Electronic address: shinsy@konkuk.ac.kr.
PMID: 39265893 DOI: 10.1016/j.bmcl.2024.129952
Abstract

To identify compounds inhibiting the activity of the Early Growth Response (EGR)-1 DNA-binding domain, thirty-seven pyrazolines were prepared and their EGR-1 DNA-binding activities were measured. Pharmacophores were derived based on quantitative structure-activity relationship calculations. As compound 2, 1-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-2-ol, showed the best inhibitory effects against the activity of the EGR-1 DNA-binding domain, the binding mode between compound 2 and EGR-1 was elucidated using in silico docking. The pharmacophores were matched to the binding modes. Electrophoretic mobility shift assays confirmed that compound 2 dose-dependently inhibited TNFα-induced EGR-1-DNA complex formation in HaCaT cells. Reverse transcription-polymerase chain reaction demonstrated that compound 2 effectively reduced the mRNA expression of EGR-1-regulated inflammatory genes, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-1β, IL-6, and IL-31, in TNFα-stimulated HaCaT cells. Therefore, compound 2 could be developed as an agent that inhibits the activity of the EGR-1 DNA-binding domain.

Keywords

Early Growth Response (EGR)-1 DNA-binding domain; In silico docking; Pyrazolines.

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