Leukemic cells exhibit dysregulation of innate immune signaling pathways upon diagnosis, and these pathways become further activated in drug resistance. The Interleukin-1 receptor associated kinase 1 and 4 (IRAK1/IRAK4) kinase complex is part of a critical signaling node that becomes activated in these dysregulated pathways (reviewed in J Bennett and DT Starczynowski, Curr Opin Hematol 2022). IRAK4 inhibitors are currently under investigation for the treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) and have shown encouraging, though modest responses in clinical studies. We have recently demonstrated that limited responses to IRAK4 inhibitors in the leukemic setting can be explained by a compensated upregulation and activation of IRAK1, and the need to inhibit both IRAK1 and IRAK4 to achieve maximal therapeutic efficacy (JR Bennett et. al., Blood 2023 https://doi-org.libproxy1.nus.edu.sg/10.1182/blood.2022018718). KME-0584 is a highly potent IRAK1/IRAK4/panFLT3 inhibitor that exhibits superior potency and therapeutic efficacy vs. IRAK4 inhibitor compounds in the FLT3 WT as well as the FLT3 mutant setting.KME-0584 exhibits >100-fold selectivity vs. 89% of the Kinome as measured in the Reaction Biology 374 kinase panel, with an IC50 of 23, <1.29, and <0.5nM at IRAK1, IRAK4, and FLT3 respectively. Higher kinase selectivity is seen in cell-based assays vs. biochemical assays, where high potency kinase antagonist activity is also observed against PHKg1, PDGFRβ, RET, CLK1, and CLK4. While IRAK4-selective compounds fully antagonize NF-κB signaling through the TLR pathway, KME-0584 completely inhibits NF-κB signaling through both the TLR and IL1-receptor pathways, indicating complete inhibition of multiple receptor pathways converging on NF-κB requires both IRAK1 and IRAK4 antagonism. In primary patient cell lines from FLT3 wildtype (WT) patients, KME-0584 inhibits leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib). This activity is independent of patient mutational status. Importantly, high potency in primary patient cell lines is observed independent of the presence of U2AF1 or SF3B1 spliceosome mutations known to drive expression of the activated IRAK4 Long isoform of IRAK4 (Fig 1), implying that the IRAK1/4/panFLT3 inhibitor KME-0584 will have activity across a broader patient population than an IRAK4 inhibitor. We have previously described an IRAK1/4 gene signature that is highly expressed in patients with myelomonocytic subtypes (M4 FAB) of adult and pediatric AML and with an antecedent MDS (JR Bennett et. al., Blood 2023 https://doi-org.libproxy1.nus.edu.sg/10.1182/blood.2022018718). The IRAK1/4 gene signature is reversed after treatment of THP1 cells for 24 hours with KME-0584. Given that monocytic-like subtypes of AML are resistant to Venetoclax plus Azacitidine (VEN/AZA) (S Pei et. al. Cancer Discovery, 2020), these data suggest that KME-0584 has the potential to be effective across a broader range of relapsed/refractory AML/MDS patients than previously examined IRAK4 inhibitors.KME-0584 exhibits superior potency and efficacy to gilteritinib in the FLT3-ITD (D835Y) xenograft model after QD oral dosing, with sufficient PK and oral bioavailability across multiple species to support QD or BID dosing in the clinic. KME-0584 does not inhibit any of the major or minor cytochrome P450 enzymes at anticipated clinical concentrations and early indication from ongoing GLP toxicology studies suggest that it could be safely administered in humans. A clinical study of KME-0584 in relapsed/refractory AML and HR-MDS is currently planned to start in 1H 2024.
