Targeting NF-kappaB-Inducing Kinase (NIK) for the Treatment of Hematologic Malignancies
Abstract
Principal Investigator s (PI s) career goals: The PI, Mr. Jian Tang, is a third-year graduate student in the Department of Medicinal Chemistry at the University of Minnesota (UMN). His short-term career goal is to obtain a postdoctoral research position in chemical biology as applied to human cancers. After postdoctoral training, Mr. Tang aspires to obtain a principal investigator position at a major research university and direct a research laboratory that is focused on mechanistic studies and therapeutic development of human blood cancers. This Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Horizon Award, if funded, will provide essential financial resources to enable the PI to complete his doctoral research project and attain a Ph.D. in medicinal chemistry. Specifically, this PRCRP project will enable the PI to achieve mastery in medicinal chemistry, as well as learn specialized skills in computational drug design and protein-small molecule structural biology. The PI will also receive advanced training in cancer biology by performing this project, supplementary graduate course work, and participation in seminars and journal clubs in the UMN Masonic Cancer Center. The mentor, Dr. Harki, will contribute to the PI s training by providing project guidance while allowing Mr. Tang to pursue independent ideas that are aligned with the goals of the project. A comprehensive training plan has been co-developed by the PI and mentor that includes opportunities for professional development (conference attendance), scientific skill development (short course), and learning of skills required for a future career as an academician (participation in UMN Preparing Future Faculty Program and mentoring undergraduate students, and collaborating with the mentor on the preparation of grants applications and manuscripts). The development of novel chemical probes to regulate non-canonical NF-kappaB signaling via targeting NF-kappaB inducing kinase (NIK) for the treatment of blood cancers (FY18 PRCRP topic areas Blood Cancers, Myeloma, and Lymphoma) will confer an outstanding training experience for the PI. Proposed research: There are currently no effective treatments for aggressive blood cancers such as multiple myeloma (MM) and mantle cell lymphoma (MCL). Therefore, targeting novel vulnerabilities in these cancers may contribute to the discovery of more efficacious therapies, which are badly needed. Dysregulated activation of the noncanonical (nc) NF-kappaB signaling pathway has been identified to be essential to promote the tumor growth of many aggressive blood cancers, including MM and MCL. Under normal conditions, this pathway is silent due to constant degradation of the central activator NIK. However, abnormal stabilization of NIK results in constitutive ncNF-kappaB signaling that drives cancer cell growth. Therefore, small molecule drugs that inhibit NIK may yield novel therapies for MM and MCL. In this project, two innovative and complementary approaches will be explored to selectively inhibit NIK. In one aim, we will develop novel compounds that result in the degradation of NIK. In the second aim, we will develop compounds that target a novel surface on NIK that may confer a better approach toward modulating this enzyme. Both aims will be rigorously pursued using techniques of medicinal chemistry, cellular and molecular biology, computational drug design, and structural biology to achieve our research objective of creating potent, selective, and safe inhibitors of NIK. If successful, our project will result in the development of novel NIK inhibitors that may ultimately be developed into human therapies. As with any drug discovery project, a significant development time (5 to 10 years) will be required for clinical development. One potential advantage of targeting NIK as a novel therapeutic strategy is the possibility of low toxicity due to the absence of NIK in most normal tissue cells. Relevance to military b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910336
Entities
People
- Jian Tang
Organizations
- United States Army
- University of Minnesota