2. Academic Validation
  3. Novel 3,6-Disubstituted Pyridazine Derivatives Targeting JNK1 Pathway: Scaffold Hopping and Hybridization-Based Design, Synthesis, Molecular Modeling, and In Vitro and In Vivo Anticancer Evaluation

Novel 3,6-Disubstituted Pyridazine Derivatives Targeting JNK1 Pathway: Scaffold Hopping and Hybridization-Based Design, Synthesis, Molecular Modeling, and In Vitro and In Vivo Anticancer Evaluation

  • ACS Omega. 2024 Aug 19;9(35):37310-37329. doi: 10.1021/acsomega.4c05250.
Mai M Shaalan 1,  Essam Eldin A Osman 2,  Yasmeen M Attia 3,  Olfat A Hammam 4,  Riham F George 2,  Bassem H Naguib 1 5
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo 11837, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
  • 3 Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo 11837, Egypt.
  • 4 Pathology Department, Theodor Bilharz Research Institute, Imbaba, Giza 12411, Egypt.
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
PMID: 39246493 DOI: 10.1021/acsomega.4c05250
Abstract

A series of novel 3,6-disubstituted pyridazine derivatives were designed, synthesized, and biologically evaluated as preclinical Anticancer candidates. Compound 9e exhibited the highest growth inhibition against most of the NCI-60 Cancer cell lines. The in vivo Anticancer activity of 9e was subsequently investigated at two dose levels using the Ehrlich ascites carcinoma solid tumor animal model, where a reduction in the mean tumor volume allied with necrosis induction was reported without any signs of toxicity in the treated groups. Interestingly, compound 9e was capable of downregulating c-jun N-terminal kinase-1 (JNK1) gene expression and curbing the protein levels of its phosphorylated form, in parallel with a reduction in its downstream targets, namely, c-Jun and c-Fos in tumors, along with restoring p53 activity. Furthermore, molecular docking and dynamics simulations were carried out to predict the binding mode of 9e and prove its stability in the JNK1 binding pocket.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-169021
    JNK1 Inhibitor
    JNK