R01CA268384

Discovery of First-in-Class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-Rearranged Leukemias - Project Summary

Rearrangements of the mixed-lineage leukemia (MLL) gene account for approximately 10% of all human leukemias. These rearrangements are more common in pediatric leukemias, with up to 80% of infant acute lymphoblastic leukemias (ALL) and 35-50% of infant acute myeloid leukemias (AML) characterized by MLL rearrangements. Unfortunately, MLL-rearranged (MLL-R) leukemia patients have a particularly poor response to standard treatments and a dismal prognosis. To date, no effective targeted therapies have been approved for treating these deadly cancers.

One potential drug target for MLL-R leukemias is WD40 repeat domain protein 5 (WDR5), an essential subunit of the MLL1 histone methyltransferase complex (MLL1 complex). WDR5 is crucial for MLL1 complex-mediated regulation of gene transcription and also interacts with non-MLL partners such as c-Myc. Interactions between WDR5 and its various binding partners are essential for sustaining oncogenesis, and genetic depletion of WDR5 suppresses the proliferation of MLL-R leukemias. Therefore, WDR5 holds promise as a drug target for MLL-R leukemias.

However, while small-molecule inhibitors that effectively block the protein-protein interactions (PPI) between WDR5 and its binding partners have been developed, these WDR5 PPI inhibitors are largely ineffective in killing MLL-R leukemia cells and lack in vivo efficacy. In contrast, genetic knockout or knockdown of WDR5 has shown a cell-killing effect. Based on this, we hypothesize that pharmacological degradation of WDR5 by small-molecule degraders as a novel therapeutic strategy will be effective and superior to pharmacological inhibition of WDR5 by PPI inhibitors for the treatment of MLL-R leukemias.

To test this hypothesis, we propose to discover first-in-class WDR5 small-molecule degraders using the proteolysis targeting chimera (PROTAC) technology and evaluate them in MLL-R leukemia cellular and mouse models. Our preliminary results have been very promising, suggesting that the proposed research is feasible. The WDR5 PROTAC degraders generated in this project will not only help us test our innovative therapeutic hypothesis but can also be further developed into a drug candidate for advancing to clinical trials with MLL-R leukemia patients. Additionally, these WDR5 PROTACs are valuable chemical probes for assessing the therapeutic potential of WDR5 degradation in other cancers.

Icahn School Of Medicine At Mount Sinai

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 377% from $671,604 to $3,200,543.