Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [1, 2, 3] (MCL1 [1, 3])

Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) is a critical anti-apoptotic member of the BCL-2 family that serves as a master regulator of the intrinsic apoptotic pathway [1, 5]. It primarily functions by sequestering pro-apoptotic BH3-only proteins and effector proteins like BAX and BAK, thereby preventing mitochondrial outer membrane permeabilization and subsequent cell death [6, 11]. MCL1 is frequently overexpressed or genetically amplified in a wide range of human malignancies, including multiple myeloma, acute myeloid leukemia, and non-small-cell lung cancer [5, 10, 15]. This overexpression is a major driver of tumorigenesis and a key mechanism of resistance to conventional chemotherapy and other BCL-2 inhibitors like venetoclax [5, 6, 18]. Therapeutic strategies focus on developing selective small-molecule inhibitors, known as BH3 mimetics, that disrupt MCL1's interaction with pro-apoptotic partners to restore the apoptotic program in cancer cells [5, 9]. However, clinical development faces significant challenges, including potential cardiotoxicity and the need for precise patient stratification using biomarkers such as MCL1 expression levels or BH3 profiling [4, 16, 18].

Other names

MCL1 [1, 3]BCL2L3 [1, 3]EAT [1, 3]Mcl-1 [1, 3]Myeloid cell leukemia 1 [1, 3]Bcl-2-like protein 3 [2, 3]Myeloid cell leukemia sequence 1 protein [2, 3]BCL2 family apoptosis regulator [1, 3]Myeloid cell factor-1 [2]

MCL-1 inhibitors primarily function as BH3 mimetics that bind to the hydrophobic BH3-binding groove of the MCL-1 protein [5, 6]. This binding prevents MCL-1 from sequestering pro-apoptotic BH3-only proteins (such as BIM, PUMA, and NOXA) and effector proteins (BAX and BAK) [11, 18]. By displacing these pro-apoptotic factors, the inhibitors facilitate mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c and the activation of the caspase cascade, which ultimately induces programmed cell death in cancer cells [5, 6, 18].