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

European Journal of Medicinal Chemistry
Satish SagarAmarnath Natarajan

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.

References

Aug 29, 1997·Journal of Medicinal Chemistry·M F Sugrue
Jul 27, 1963·Nature·H C RICHARDSD F SPOONER
May 13, 2005·Journal of Medicinal Chemistry·Jotham W CoeBrian T O'Neill
Jul 30, 2005·The Journal of Organic Chemistry·Amarnath NatarajanMichael Chorev
Sep 30, 2005·BMC Genomics·Bing TianAllan R Brasier
Oct 31, 2006·Oncogene·T D Gilmore, M Herscovitch
Apr 5, 2007·Nature Protocols·Nicolaas A P FrankenChris van Bree
Mar 20, 2010·Cold Spring Harbor Perspectives in Biology·Alain Israël
Mar 8, 2011·Bioorganic & Medicinal Chemistry Letters·Qianyi ChenAmarnath Natarajan
Jun 28, 2011·The Journal of Clinical Investigation·Katerina VlantisManolis Pasparakis
Dec 6, 2011·Bioorganic & Medicinal Chemistry Letters·Vashti C BryantAmarnath Natarajan
Feb 14, 2012·Nature Cell Biology·Yifeng XiaInder M Verma
Mar 6, 2012·Bioorganic & Medicinal Chemistry·Rajkumar RajuleAmarnath Natarajan
Mar 23, 2012·Immunological Reviews·Fei LiuInder M Verma
Mar 23, 2012·Immunological Reviews·Joseph A DiDonatoMichael Karin
Aug 16, 2012·Proceedings of the National Academy of Sciences of the United States of America·Helena ShakedMichael Karin
Oct 16, 2012·Chemical Research in Toxicology·Lisa A Peterson
Nov 20, 2012·Organic & Biomolecular Chemistry·Sandeep Rana, Amarnath Natarajan
Feb 28, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Prakash RadhakrishnanAmarnath Natarajan
Apr 11, 2013·Scientific Reports·Eric A KumarAmarnath Natarajan
Aug 22, 2013·Molecular Cancer Therapeutics·Nagendra K ChaturvediShantaram S Joshi
Jul 12, 2014·European Journal of Medicinal Chemistry·Joana A PereiraMónica Vieira
Nov 1, 2015·Immunology Letters·Dulce MaroniMayumi Naramura
May 11, 2016·Current Medicinal Chemistry·Thanigaimalai PillaiyarManoj Manickam
Aug 3, 2016·Anti-cancer Agents in Medicinal Chemistry·Maria Letícia de Castro BarbosaViviane de Oliveira Freitas Lione
Oct 21, 2016·Current Opinion in Pharmacology·John A McCauley, Michael T Rudd

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Citations

Nov 20, 2021·The Journal of Organic Chemistry·Yumiko SuzukiNoriyuki Suzuki

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