BCL2 Target Analysis Report Summary
About the Target
BCL-2, also referred to as B-cell lymphoma-2, is a protein that plays a crucial role in determining cell survival or cell death through apoptosis. It is involved in maintaining cellular homeostasis by regulating the balance between pro-apoptotic and anti-apoptotic proteins [3].
Anti-apoptotic proteins, including BCL-2, BCL-XL, BCL-W, and MCL-1, bind to the pro-apoptotic molecules BID and BIM [1][2]. This binding prevents the activation of BAX and BAK, which are responsible for initiating mitochondrial outer membrane permeabilization (MOMP) and subsequently leading to apoptosis [1]. By antagonizing the activator and effector molecules, the anti-apoptotic proteins block the apoptotic cascade [2].
However, cell death signals also activate sensitizer molecules, such as BH3-only proteins like BIM, BID, PUMA, NOXA, and BAD [2]. These sensitizer molecules displace or prevent the anti-apoptotic proteins from binding to BAX and BAK, allowing for cytochrome c release into the cytosol and activation of the caspase cascade, resulting in cell death [2].
The balance between pro- and anti-apoptotic BCL-2 proteins is essential for maintaining cellular homeostasis [3]. In a prosurvival mode, BAK/BAX interacts with antiapoptotic BCL-2 proteins, thereby preventing the execution of the apoptotic program and allowing cells to survive [3]. In contrast, activation of BAK/BAX can occur under stress or upon receiving upstream signals that act on the BH3-only proteins, leading to apoptosis [3].
Navitoclax, a potential therapeutic agent, interacts with antiapoptotic BCL-2 family proteins to potentiate apoptotic activity [4]. CS055, another compound, induces DNA double-strand break accumulation and alters the balance of pro-apoptotic and anti-apoptotic Bcl-2 proteins [5]. This alteration, along with the inhibition of Bcl-2 by ABT-199 and downregulation of Mcl-1 and Bcl-xL by CS055, can induce apoptosis and potentially overcome resistance to ABT-199 in acute myeloid leukemia (AML) cells [5].
In summary, BCL-2 proteins play a critical role in determining cell survival or cell death through the regulation of apoptosis. Anti-apoptotic BCL-2 proteins bind to pro-apoptotic molecules, preventing the initiation of apoptosis. However, sensitizer molecules can displace or prevent the binding of anti-apoptotic proteins, leading to cell death. The balance between pro- and anti-apoptotic BCL-2 proteins is crucial for maintaining cellular homeostasis. Therapeutic agents, such as navitoclax and CS055, interact with BCL-2 family proteins to potentiate apoptosis and potentially overcome resistance in certain cancers.
Based on the provided context information, the BCL-2 family of proteins plays a critical role in regulating apoptosis, the programmed cell death process. These proteins can be classified as anti-apoptotic (pro-survival) or pro-apoptotic (pro-death), and they interact with each other through binding selectivity profiles [6]. Pro-apoptotic proteins can initiate apoptosis by various mechanisms, such as activating effector proteins, promoting their insertion into mitochondrial membranes, and preventing anti-apoptotic proteins from sequestering pro-apoptotic effectors [6].
In the context of cancer treatment, small-molecule BH3 mimetics like venetoclax have been designed to bind competitively to anti-apoptotic proteins, liberating pro-apoptotic proteins and triggering apoptosis in cancer cells [6]. These BH3 mimetics have shown selective cytotoxic and antiviral activities [7]. Furthermore, melatonin treatment has been found to induce mitochondrial-mediated cell death in cancer cells by reducing the mitochondrial electron transport chain, generating reactive oxygen species, down-regulating BCL-2, and releasing AIF (apoptosis-inducing factor) [8].
The expression levels of BCL-2 family genes, specifically the BCL2/BCL2L1 ratio, have been found to correlate with sensitivity to BCL2 inhibitors like venetoclax in multiple myeloma (MM) and primary plasma cell leukemia (pPCL) [9]. The presence of the t(11;14) translocation has been associated with higher expression levels of BCL2 family genes in MM and pPCL, which may contribute to increased sensitivity to BCL2 inhibitors [9].
BH3-only proteins can play a role in apoptosis by interacting with anti-apoptotic BCL-2 family members [10]. However, the requirement of BH3-only proteins in apoptosis regulated by both BCL-XL and MCL-1 remains unclear, as the neutralization of anti-apoptotic proteins with BH3 mimetics can still induce apoptosis in the absence of all eight BH3-only proteins [10]. Other BH3-domain containing proteins not classified as the key BH3-only members may interact with BCL-XL and MCL-1 and contribute to apoptosis [10].
Overall, the BCL-2 family of proteins and their interactions play a crucial role in regulating apoptosis, and targeting these proteins or their interactions with BH3 mimetics holds promise for cancer treatment. Different BCL-2 inhibitors and melatonin have shown cytotoxic and antiviral activities and can induce selective apoptosis in cancer cells. The expression levels of BCL2 family genes, particularly the BCL2/BCL2L1 ratio, may serve as predictive markers for the sensitivity to BCL2 inhibitors. However, the exact role of BH3-only proteins in apoptosis and the involvement of other BH3-domain containing proteins require further investigation [6][7][8][9][10].
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Note: If you are interested in the full version of this target analysis report, or if you'd like to learn how our AI-powered BDE-Chem can design therapeutic molecules to interact with the BCL2 target at a cost 90% lower than traditional approaches, please feel free to contact us at BD@silexon.ai.
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