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NIH Research Festival

September 23 – 25, 2024

Assay Development for the identification of ALPK1 inhibitors

Authors

  • NJ Martinez
  • A Zakharov
  • G Rai
  • SI Son
  • D Esposito
  • JP Denson
  • C Kozycki
  • D Kastner
  • A Simeonov

Abstract

Alpha-kinase 1 (ALPK1) is a member of the atypical kinases that functions as an innate immune sensor by binding ADP-heptose, a bacterial sugar. This binding leads to activation of the TIFA-TRA6 signaling axis, leading to NF-kB activation and cytokine production. Activating mutations on Thr237 and Tyr254 residues of ALPK1 are the root cause of a dominantly inherited autoinflammatory disorder, ROSAH, associated with progressive blindness, periodic fevers, and debilitating headaches. These mutations render ALPK1 constitutively active, resulting in cytokine production even in the absence of ADP-heptose. Hence, inhibition of this signaling axis is expected to ameliorate symptoms of the disease. While inhibition of TIFA and NF-kB would be associated with considerable side effects and intolerable immunosuppression given that these proteins are converging points of multiple signaling pathways, inhibition of ALPK1 constitutes a more specific strategy. TIFA is the only known and validated target of ALPK1. In addition to ROSAH, ALPK1 has been linked to other disorders of inflammation including Helicobacter pylori associated cancers, inflammatory bowel disease, and gout. However, studies to further dissect the role of ALPK1 signaling are currently limited by the lack of ALPK1 inhibitors. Even known promiscuous inhibitors of typical kinases such as staurosporine, have no effect on ALPK1. Therefore, the discovery of a small molecule probe against ALPK1 would greatly benefit the study of ALPK1 function as well as constitute starting points for therapeutic development. To this end, we are developing and evaluating cell-based and biochemical assays amenable to the high-throughput screening of small molecule libraries.

Scientific Focus Area: Chemical Biology

This page was last updated on Tuesday, August 6, 2024

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Current Research Festival

  • 2025
  • 2024
    • General Schedule of Events
    • 2024 NIH Distinguished Scholars Program
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    • Concurrent Workshops
    • NIH Resource Information Fair
    • National Academy of Science Mini-Symposium
    • Special Wednesday Events
    • Vendor Exhibit Information
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    • Research Festival Committee
  • 2023
    • General Schedule of Events
    • NIH Early–Career Investigator Lectures
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    • Concurrent Workshops
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    • Vendor Exhibit Information
    • Research Festival Committee
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