MDS and AML are blood cell cancers with a large patient burden. Collectively, more than 30,000 new cases of MDS and AML are diagnosed in the United States each year. Patients are typically treated with chemotherapy and, in some cases, stem cell transplantation, but durable remission often remains elusive. As a result, the median survival time for MDS is only 2.5 years after diagnosis, and the 5-year survival rate for AML is only 27 percent. Improved treatments for MDS and AML are urgently needed.
Scientific Synopsis
The IRAK1/4 and FLT3 kinase enzymes play key roles in cell signaling pathways that drive the progression of MDS and AML. Small molecule inhibitors of FLT3 have advanced into Phase II clinical trials and have demonstrated proof-of-concept in the treatment of AML. However, these initially promising results have been tempered by the realizations that inhibition of FLT3 signaling can lead to increased compensatory signaling through the IRAK pathway and that cancerous cells can develop mutant forms of FLT3 that are not blocked by the first-generation inhibitors. Both the compensatory signaling through IRAK and the development of FLT3 mutations render single-acting FLT3 inhibitors less effective over time. The goal of this project is to develop dual-acting inhibitors of both IRAK and FLT3. Small molecule inhibitors that block signaling through both pathways and that inhibit not only the most common form of FLT3 but also its mutant forms should be more effective as long-term treatments for MDS and AML.
Medicinal chemistry efforts in the teams’ laboratories have led to the discovery of lead compound NCGC-1481, a highly potent inhibitor of IRAK1/4, FLT3, and many of the most common mutant forms of FLT3. In the MA9-FLT3-ITD cancer cell line, which contains a mutant form of FLT3, compounds from this series effectively block compensatory signaling through IRAK1/4. These compounds also block the growth and proliferation of MA9-FLT3-ITD cancer cells. In a mouse xenograft model of AML, NCGC-1481 produced an increase in survival time comparable to that of the Phase II candidate AC220. This is notable, given the fact that NCGC-1481 is not yet a fully optimized compound. Current efforts are aimed at further improving the properties of compounds in this series, with the ultimate goal of advancing an optimized candidate into clinical trials as a treatment for MDS and AML.
This figure illustrates the chemical structure of lead compound NCGC-1481. The bar graph in the center indicates the numbers of MA9-FLT3-ITD cancer cells remaining (colony number) after treatment with control (black bar on far left), the Phase II FLT3 inhibitor AC220 (gray bar that is second to left), NCGC-2327 (red bar that is third from the left), or NCGC-1481 (blue bar that is fourth from the left). The line graph on the right indicates the percentage of mice surviving after xenograft transplant upon treatment with control (black line on left), AC220 (red line on the left), or NCGC-1481 (blue line in the middle).
Lead Collaborators
- Craig J. Thomas, Ph.D., NCATS, NIH
- Scott B. Hoyt, Ph.D., NCATS, NIH
- Dan Starcyznowski, Ph.D., Cincinnati Children’s Hospital
Public Health impact
This project provides insight into the effects of dual-acting IRAK/FLT3 inhibitors in cancer cell lines and animal models and may yield an optimized candidate for MDS/AML clinical trials.