First-in-Class, Dual Degraders of IRAK 1 and IRAK 4 for MyD88-Mutant Blood Cancers

Project Overview

• Many blood cancers like B-cell malignancies, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) with mutations in the MyD88 gene, which controls an inflammatory signaling pathway, remain incurable with few treatment options and frequent development of resistance.
• MyD88 signaling is mediated by a family of enzymes known as IRAK kinases.
• A team of Dana-Farber researchers has developed a portfolio of the first dual IRAK1/4 degraders as potential treatments for these cancers.
• Dana-Farber has a broad portfolio of IRAK1/4 degraders and IRAK 1 inhibitors available for licensing; Collaborative development opportunities are also available.

Technology

The MyD88 gene plays a crucial role in regulating a signaling pathway for inflammatory cytokines. Mutations in the MyD88 gene are common and have been linked to the development of certain blood cancers, such as Waldenström’s macroglobulinemia and several B-cell lymphomas.

Unfortunately, there are currently no curative treatments for blood cancers with MyD88 mutations. Patients may need to undergo treatment for up to 10 years, with limited options including chemo-immunotherapy, proteasome inhibitors, and targeted therapy with drugs like ibrutinib that target Bruton’s tyrosine kinase (BTK). However, even with treatment, resistance often develops, and the cancer can become more aggressive.

Recent research has shed light on the complex signaling mechanisms involving MyD88. It has been discovered that this critical signaling component can be influenced by multiple interaction partners. One of the prominent partners is the IL-1R-associated kinase (IRAK) family of enzymes, particularly IRAK1 and IRAK4, which have been found to contribute to abnormal inflammatory signaling that promotes the growth and spread of malignant cells. Previous studies have shown that some patients only partially respond to BTK treatment due to persistent activity of IRAK1 and IRAK4, which leads to the cancer cells adopting a pro-survival mode. However, inhibiting both IRAK 1 and IRAK 4 triggers apoptosis – or cancer cell death – in patients on prolonged ibrutinib therapy, representing a new mode of strategy for treating MyD88-mutated cancers.

Dana-Farber researchers, led by Steven Treon, MD, PhD, Sara Buhrlage, PhD, and John Hatcher, PhD, have achieved a significant breakthrough by developing first-of-their-kind compounds that effectively degrade both IRAK 1 and IRAK4. These pioneering compounds exhibit exceptional potency and selectivity. Furthermore, they display favorable characteristics resembling those of potential drugs and have shown promising results in laboratory studies involving blood cancers.

Along with having their own enzymatic activity,  when IRAK 1 and IRAK 4 proteins interact with each other they co-mingle to form a scaffolding backbone complex with its own pro-cancer function.  Because the two proteins are so closely aligned in the scaffold, they interact and integrate with each other more readily. That IRAK 1/4 scaffolding structural effect holds the proteins together, enhancing their ability to promote cancer growth.

The IRAK1/4 degraders created by the Dana-Farber team destroy the complex, including IRAK 1 and IRAK 4, so they can no longer play a role in cancer development and spread.

The team’s in vitro studies in Waldenström’s macroglobulinemia, activated B-cell diffuse large B-cell lymphoma (ABC DLBCL), and AML found that the IRAK1/IRAK4 dual degraders have superior cell killing efficacy over IRAK4 degraders and IRAK1/IRAK4 dual enzymatic inhibitors.  In addition, the combination of IRAK1/IRAK4 degraders with ibrutinib improves tumor cell killing over ibrutinib alone. This represents a potentially powerful double-drugging strategy highlighting the strategic benefit of dual protein degradation of IRAK 1/4.  

Compounds from other researchers are categorized as IRAK4 degraders but it is unclear if they degrade both IRAK1 and IRAK4. 

The team also developed a portfolio of the first and only known IRAK1 inhibitors. In 2017, they published a paper in the Proceedings of the National Academy of Sciences that first revealed the structure of the IRAK1 kinase when paired with a small molecule inhibitor. In the same year, they also published a report in the journal Blood that demonstrated the synergistic effect of their lead IRAK1 inhibitor when combined with the BTK inhibitor, ibrutinib, in MyD88-mutated B-cell lymphoma cells.

Thanks to their extensive expertise in MyD88-mutated diseases and their long-standing medicinal chemistry program, the researchers have successfully tested and optimized several IRAK1 inhibitors that can maintain necessary drug levels for treating disease. They have also developed highly potent and selective dual inhibitors of IRAK1 and IRAK4 where IRAK1 is irreversibly inhibited, and IRAK4 is reversibly inhibited. These compounds are showing encouraging potency in Waldenstrom’s Macroglobulinemia (WM), activated B-cell diffuse large B-cell lymphoma (ABC DLBCL), and AML cell lines.

The team has created an integrated development plan to advance both the IRAK1/4 degrader and IRAK1 inhibitor programs in parallel.

Team Members: Steven P. Treon, MD, PhD, Sara Buhrlage, PhD, John Hatcher, PhD

Applications

IRAK1/4 degraders have been developed to target diseases with mutations in the MYD88 gene including B-cell lymphomas, MDS, and AML. Many MyD88-mutated B-cell lymphomas – including WM, ABC, DLBCL, primary CNS lymphoma (PCNSL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL), involve relatively small patient populations individually,  but when considered together, they affect a significant number of patients lacking effective long-term treatments. Many of these patients are currently undergoing long-term treatment with BTK therapies. 

Adding IRAK1/4 degraders may serve as an alternative treatment option once resistance to BTK therapies develops, or in combination with BTK inhibitors or other compounds to enhance their effectiveness against cancer.

Opportunities

Dana-Farber is interested in licensing its IRAK1/4 and/or IRAK1 portfolios to partners interested in developing new clinical compounds to treat MYD88-mutated diseases.  Collaborative development opportunities are also available for both programs.

Team Members

Steven P. Treon, MD, PhD

Senior Physician, Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital

Associate Professor of Medicine, Harvard Medical School

Steven's Bio

Sara Buhrlage, PhD

Principal Investigator, Cancer Biology, Dana-Farber

Associate Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School

Sara's Bio

John Hatcher, PhD

Principal Scientist, Medicinal Chemistry Core, Dana-Farber

John's Bio