Bcl-2-related protein A1 (BFL-1) (BFL-1)

BFL-1 (BCL2A1) is a pro-survival member of the Bcl-2 family that plays a critical role in inhibiting apoptosis by sequestering pro-apoptotic proteins like BIM, BAX, and BAK [1, 2]. It is a direct transcriptional target of NF-kappa B and is primarily expressed in the hematopoietic system, where it supports the survival of leukocytes during inflammation [3, 4]. In many cancers, including melanoma and various leukemias, BFL-1 is overexpressed and serves as a major mechanism of resistance to chemotherapy and targeted therapies like the BCL-2 inhibitor venetoclax [5, 6]. Because BFL-1 knockout mice exhibit minimal physiological defects, it is considered an attractive therapeutic target with a potentially wide therapeutic window [4, 6]. Current drug development efforts focus on creating selective BH3 mimetics that can disrupt BFL-1's interaction with pro-apoptotic factors to sensitize tumor cells to apoptosis [7, 8].

Other names

BCL2A1BFL1GRSHBPA1ACC-1ACC-2BCL2L5Hemopoietic-specific early response proteinA1

BFL-1 inhibitors function as BH3 mimetics that competitively bind to the hydrophobic groove of the protein, preventing it from sequestering pro-apoptotic BH3-only proteins (e.g., BIM, PUMA, NOXA) and effector proteins (BAX, BAK), thereby restoring the intrinsic apoptotic pathway and inducing mitochondrial outer membrane permeabilization [2, 7].