Therapeutic targeting of IRF4 to treat multiple myeloma
Stephen Nutt
PhDWalter & Eliza Hall Institute of Medical Research
Project Term: July 1, 2019 - June 30, 2022
Multiple myeloma is an incurable malignancy derived from transformed plasma cells. The transcription factor IRF4 is essential for the survival of myeloma and thus represents an excellent potential drug target. We have devised a strategy to identify the key amino acid residues, binding surfaces and protein partners of IRF4 and now aim to screen for small molecule inhibitors of this factor. Lead molecules will be developed that either directly inhibit IRF4 function or promote its degradation.
Plasma cells are a specialized cell type that produce the antibodies that are essential to protect us from microorganisms and provide the basis for the beneficial effects of immunization. Multiple myeloma (MM) is a form of cancer that arises from altered plasma cells whose number can no longer be appropriately controlled and is one of the most common blood cancers. Despite considerable advances in treatments options in recent years, MM remains incurable.
Work from a number of researchers, including us, has identified a regulatory protein called IRF4 as being essential for MM cell survival. Thus, we predict that a drug that blocks IRF4 function would represent an excellent new approach to treat MM. Unfortunately, IRF4 belongs to a family of regulatory proteins that have traditionally been considered to be difficult to develop drugs against and thus new and innovative approaches are needed.
To overcome these hurdles, we have developed a system to interrogate the IRF4 protein for points of weakness that could be exploited by new therapeutics. Having identified specific sites on the IRF4 protein that are essential for its function and are thus ideal new targets for drug development, we will now screen large collections of small drug-like molecules for those that bind to and inhibit IRF4 function. These “hits” will be further developed into “lead” molecules that can be tested in more complex models that more closely resemble the situation in individuals with MM. If successful these leads can be for further optimized for eventual testing in MM patients.
In summary, a wealth of data we and other researchers have produced, supports the idea that inhibiting IRF4 function represents an exciting approach for the effective treatment of MM. We have developed a new experimental system to probe the IRF4 molecule to identify new areas of weakness and aim to translate this knowledge into anti-IRF4 drugs that we can rapidly develop into new potential treatments for MM.