KME-0584: A Novel IRAK1/IRAK4/panFLT3 Inhibitor for Relapsed/Refractory AML/MDS with Resistance to Hypomethylating Agents and Venetoclax

The text discusses leukemic cells' immune signaling pathway dysregulation and their further activation in drug resistance. It mentions that IRAK1/IRAK4 kinase complex plays a key role in these pathways. IRAK4 inhibitors are being studied for treating AML and MDS with modest clinical responses. The limited efficacy of IRAK4 inhibitors is attributed to the upregulation and activation of IRAK1, suggesting the necessity to inhibit both IRAK1 and IRAK4 for optimal therapeutic effect.

KME-0584 is a potent inhibitor of IRAK1/IRAK4/panFLT3, showing superior potency and efficacy compared to IRAK4 inhibitors in both FLT3 WT and mutant settings. It is highly selective with low IC50 values for IRAK1, IRAK4, and FLT3. KME-0584 also exhibits high kinase selectivity and activity against various kinases.

The compound completely inhibits NF-κB signaling through both TLR and IL1-receptor pathways, indicating the need for IRAK1 and IRAK4 antagonism to inhibit multiple receptor pathways. KME-0584 is more potent than IRAK4 inhibitors lacking IRAK1 activity in inhibiting leukemia stem cell progenitor function in primary patient cell lines. Its efficacy is not affected by patient mutational status or the presence of certain spliceosome mutations.

The text also notes that KME-0584 reverses an IRAK1/4 gene signature associated with myelomonocytic subtypes of AML and MDS. This suggests that KME-0584 could be effective in a broader range of patients resistant to other treatments. It shows superior potency and efficacy to another drug in a specific xenograft model and has suitable pharmacokinetics for clinical dosing.

A clinical trial for KME-0584 in relapsed/refractory AML and HR-MDS is planned to commence in the first half of 2024.