Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth

John Victor Napoleon, Satish Sagar, Sydney P. Kubica, Lidia Boghean, Smit Kour, Hannah M. King, Yogesh A. Sonawane, Ayrianne J. Crawford, Nagsen Gautam, Smitha Kizhake, Pawel A. Bialk, Eric Kmiec, Jayapal Reddy Mallareddy, Prathamesh P. Patil, Sandeep Rana, Sarbjit Singh, Janani Prahlad, Paul M. Grandgenett, Gloria E.O. Borgstahl, Gargi GhosalYazen Alnouti, Michael A. Hollingsworth, Prakash Radhakrishnan, Amarnath Natarajan

Research output: Contribution to journalArticlepeer-review

Abstract

Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKβ and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKβ is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKβ in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKβ inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKβ but inhibited the IKKβ kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKβ phosphorylation was inhibited by 39-100, thus we termed it IKKβ activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKβ levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKβ activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway.

Original languageEnglish (US)
Pages (from-to)e2115071119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number18
DOIs
StatePublished - May 3 2022

Keywords

  • IKKβ
  • MAP3K1
  • NF-κB
  • pancreatic cancer
  • quinoxaline

ASJC Scopus subject areas

  • General

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