Targeting NF-kappaB Inducing Kinase (NIK) for the Treatment of Hematologic Malignancies
Abstract
Deregulated activation of noncanonical (nc)NF-kappaB signaling has been identified to drive the proliferation of many hematologic cancers. The central activator of ncNF-kappaB signaling is NF-kappaB inducing kinase (NIK). We hypothesize that selective small molecule inhibitors of NIK may yield effective therapeutic strategies for the treatment of hematologic cancers. In this project, we will investigate two complementary approaches to develop selective NIK inhibitors and evaluate them in blood cancer cells with NIK accumulation. The first approach is to develop selective NIK chemical degraders through rational design of bifunctional proteolysis targeting chimeras (PROTACs) to restore the natural NIK degradation mechanism. The second approach is to develop first-in-class allosteric NIK modulators. Biochemical and crystallography studies are in progress to validate and fully characterize these inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1190562
Entities
People
- Daniel A Harki
- Jian Tang
Organizations
- University of Minnesota