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

Satish Sagar1, Sarbjit Singh1, Jayapal Reddy Mallareddy1

  • 1Eppley Institute for Cancer Research, Omaha, NE, USA.

European Journal of Medicinal Chemistry
|June 7, 2021
PubMed

Insights

A novel quinoxaline urea analog, 84, effectively inhibits NF-κB signaling and pancreatic cancer growth by targeting IKKβ. This compound demonstrates improved potency and oral bioavailability, showing promise for pancreatic cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Genetic models identify Inhibitor of nuclear factor (NF)-κB kinase beta (IKKβ) as a therapeutic target for KRAS-mutated pancreatic cancer.
  • Phosphorylation of IKKβ at S177/S181 is crucial for TNFα-induced NF-κB activation, driving cancer progression.

Purpose of the Study:

  • To optimize a previously identified NF-κB inhibitor (quinoxaline analog 13-197) through structure-activity relationship (SAR) studies.
  • To develop a novel analog with enhanced potency and oral bioavailability for pancreatic cancer treatment.

Main Methods:

  • Conducted SAR study on quinoxaline analogs to identify improved inhibitors of IKKβ.
  • Assessed inhibition of p-IKKβ levels, TNFα-induced NF-κB activity, and pancreatic cancer cell growth in vitro.
  • Evaluated pharmacokinetic properties (exposure, oral bioavailability) and in vivo efficacy in a pancreatic cancer xenograft model.

Main Results:

  • Identified quinoxaline urea analog 84, which dose- and time-dependently reduced p-IKKβ levels.
  • Analog 84 showed 2.5-fold greater potency in NF-κB inhibition and 4-fold greater potency in inhibiting cancer cell growth compared to analog 13-197.
  • Analog 84 exhibited 4.3-fold greater exposure and 5.7-fold increased oral bioavailability versus analog 13-197.

Conclusions:

  • Novel analog 84 demonstrates superior efficacy and pharmacokinetic properties over the parent compound.
  • Oral administration of analog 84, alone or with gemcitabine, effectively reduced p-IKKβ and inhibited tumor growth in vivo.
  • Analog 84 represents a promising therapeutic candidate for KRAS-mutated pancreatic cancer.
Keywords:
IKKβNFκBPancreatic cancerQuinoxaline urea

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