First-in-Class Suppressor of the TLR Pathway
(Oral, Small Molecule IRAK4 Kinase Inhibitor)
Innate immune responses orchestrated through Toll-like receptors or certain interleukin receptors are important mediators of the body’s initial defense against foreign antigens, while their dysregulation is associated with certain inflammatory conditions, including cancer. Toll-like receptors (TLRs) and the IL-1 receptor (IL-1R) family signal through the adaptor protein MYD88, that results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. More recently it has been recognized that both mutation of proteins within the TLR/IL-1R pathway may lead to hyperactive signaling and increased NF-κB activity, and the promotion of cancer. For example, intragenic mutation within MYD88 , e.g., a mutation encoding MYD88-L265P which causes activation of this pathway, is shown to occur in approximately 30% of Activated B-Cell (ABC) subtype of diffuse large B-cell lymphomas (DLBCL)1,2 and in over 90% of the B-cell malignancy Waldenstrom’s macroglobulinemia.3
Additionally, mutations in genes controlling spliceosome machinery have also been shown to activate this pathway. Recently, oncogenic mutations in RNA splicing proteins U2AF1 and SF3B1 have been detected in patients with MDS/AML4,5. Using AML patient samples, global analysis of exon usage identified IRAK4 as the most dominant alternatively-spliced isoform. Moreover Smith et al. identified a specific alternatively spliced isoform of IRAK4 denoted “IRAK4-L” (for IRAK4 Long form), which encodes a mutant IRAK4 protein with an additional exon. This increases IRAK4 interaction with the Myddosome protein complex, resulting in maximum pathway activation. Inhibition of IRAK4-L kinase activity with CA-4948 abolished leukemic growth in non-clinical experiments with AML cells.
Because IRAK4’s plays a central role in this pathway it is considered an attractive target for generation of therapeutics to treat these B-cell malignancies as well as certain inflammatory diseases.
As part of the collaboration with Aurigene, in October 2015, Curis exclusively licensed a program of orally-available, small molecule inhibitors of IRAK4 kinase, including CA-4948.
For more information on current trials click here.
Posters and Presentations
1Nature. 2011; 470(7332):115–119
2Immunology and Cell Biology. 2011; 89(6):659–660
3N Engl J Med. 30, 2012; 367(9):826–833
4Smith MA, Choudhary GS, Pellagatti A, et al., U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nat Cell Biol. 2019 May;21(5):640-650. https://doi.org/10.1038/s41556-019-0314-5
5Choudhary GS, Smith MA, Pellagatti A, et al., SF3B1 mutations induce oncogenic IRAK4 isoforms and activate targetable innate immune pathways in MDS and AML. Blood. (2019) 134 (Supplement_1): 4224. https://doi.org/10.1182/blood-2019-1244583