Structure activity relationship (SAR) study identifies a quinoxaline urea analog that modulates IKKβ phosphorylation for pancreatic cancer therapy

Satish Sagar, Sarbjit Singh, Jayapal Reddy Mallareddy, Yogesh A. Sonawane, John V. Napoleon, Sandeep Rana, Jacob I. Contreras, Christabelle Rajesh, Edward L. Ezell, Smitha Kizhake, Jered C. Garrison, Prakash Radhakrishnan, Amarnath Natarajan

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic models validated Inhibitor of nuclear factor (NF) kappa B kinase beta (IKKβ) as a therapeutic target for KRAS mutation associated pancreatic cancer. Phosphorylation of the activation loop serine residues (S177, S181) in IKKβ is a key event that drives tumor necrosis factor (TNF) α induced NF-κB mediated gene expression. Here we conducted structure activity relationship (SAR) study to improve potency and oral bioavailability of a quinoxaline analog 13–197 that was previously reported as a NFκB inhibitor for pancreatic cancer therapy. The SAR led to the identification of a novel quinoxaline urea analog 84 that reduced the levels of p-IKKβ in dose- and time-dependent studies. When compared to 13–197, analog 84 was ∼2.5-fold more potent in TNFα-induced NFκB inhibition and ∼4-fold more potent in inhibiting pancreatic cancer cell growth. Analog 84 exhibited ∼4.3-fold greater exposure (AUC0-∞) resulting in ∼5.7-fold increase in oral bioavailability (%F) when compared to 13–197. Importantly, oral administration of 84 by itself and in combination of gemcitabine reduced p-IKKβ levels and inhibited pancreatic tumor growth in a xenograft model.

Original languageEnglish (US)
Article number113579
JournalEuropean Journal of Medicinal Chemistry
Volume222
DOIs
StatePublished - Oct 15 2021

Keywords

  • IKKβ
  • NFκB
  • Pancreatic cancer
  • Quinoxaline urea

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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