The myeloid cell leukaemia-1 inhibitor MIK665 is a potent therapy in preclinical models of paediatric acute myeloid leukaemia.

Paediatric acute myeloid leukaemia (AML) remains a deadly disease, with survival rates reaching a plateau despite treatment with high-intensity chemotherapy. Recent advancements in therapeutic strategies, such as targeted therapies to inhibit AML dependencies, have aimed to improve outcomes. The evasion of apoptosis, regulated by the B-cell lymphoma 2 (BCL2) family of proteins, is a key feature of cancer progression and treatment resistance. Bcl-2 homology domain 3 (BH3) mimetics, such as venetoclax (ABT-199), which targets BCL2, have shown promising activity in AML. This study investigates for the first time the therapeutic potential of MIK665, a BH3 mimetic targeting myeloid cell leukaemia-1 (MCL1), in paediatric AML. We evaluated the efficacy of MIK665 against a diverse panel of AML cell lines and demonstrated its effectiveness as a single-agent treatment. Additionally, MIK665 showed significant activity against a subset of paediatric AML patient-derived xenografts (PDXs) in both ex vivo and in vivo experiments, with minimal impact on cardiac tissue pathophysiology. These findings strongly support the clinical advancement of MIK665 for paediatric AML treatment in a precision medicine approach.