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 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 mutations within MYD88, which cause activation of this pathway, are found in nearly 40% 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 been shown to activate this pathway. Recently, oncogenic mutations in splicing factor genes U2AF1 and SF3B1 have been detected in patients with MDS/AML.4,5,6 Using AML patient samples, global analysis of exon usage revealed enrichment of inflammatory and immune pathway genes, with IRAK4 being the dominant alternatively-spliced isoform, resulting in aberrant production of the cancer-causing “IRAK4-L” (for IRAK4 Long form). IRAK4-L causes uncontrolled activation of the myddosome protein complex and downstream NF-κB activation. Inhibition of IRAK4-L activity with emavusertib (CA-4948) blocks leukemic growth in non-clinical experiments.
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 emavusertib (CA-4948).
For more information on current trials click here.
1 Ngo VN, Young RM, et al., Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011; 470(7332):115–119. https://doi.org/10.1038/nature09671
2 Jeelall YS, Horikawa K, Oncogenic MYD88 mutation drives Toll pathway to lymphoma. Immunology and Cell Biology. 2011; 89(6):659–660. https://doi.org/10.1038/icb.2011.31
3 Treon SP, et al., MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012 Aug 30;367(9):826-33. https://doi.org/10.1056/nejmoa1200710
4 Smith 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
5 Choudhary 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-2019-124458
6 Ochi, Y., Ogawa, S., Chromatin-Spliceosome Mutations in Acute Myeloid Leukemia. Cancers. 2021, 13, 1232. https://doi.org/10.3390/cancers13061232