A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network

  • Molecules. 2025 Apr 30;30(9):2001. doi: 10.3390/molecules30092001.
Lidia Boghean  1 ,  Sarbjit Singh  1 ,  Kiran K Mangalaparthi  2 ,  Smitha Kizhake  1 ,  Lelisse Umeta  1 ,  Donn Wishka  3 ,  Paul Grothaus  3 ,  Akhilesh Pandey  2  4 ,  Amarnath Natarajan  1  5
Affiliations
  • 1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 2. Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 3. Drug Synthesis and Chemistry Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 4. Department of Community Medicine, Manipal Academy of Higher Education, Manipal 576104, India.
  • 5. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
PMID: 40363807 DOI: 10.3390/molecules30092001
Abstract

The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (51-106) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability. We used the small molecule MAP3K1 inhibitor in a proteomics study that identified NPM1 as a member of the MAP3K1 network.

Keywords
MAP3K1 inhibitor; NPM1; phosphoproteomics; quinoxaline.
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