1. Signaling Pathways
  2. Apoptosis
  3. Bcl-2 Family

Bcl-2 Family

Bcl-2 is a family of evolutionarily related proteins. These proteins govern mitochondrial outer membrane permeabilization (MOMP) and can be either pro-apoptotic (Bax, Bad, Bak and Bok among others) or anti-apoptotic (including Bcl-2 proper, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date. Human genes encoding proteins that belong to this family include: Bak1, Bax, Bal-2, Bok, Mcl-1.

Cat. No. Product Name Effect Purity
  • HY-15531
    Venetoclax Inhibitor 99.95%
    Venetoclax (ABT-199; GDC-0199) is a highly potent, selective and orally bioavailable Bcl-2 inhibitor with a Ki of less than 0.01 nM. Venetoclax induces autophagy.
  • HY-10087
    Navitoclax Inhibitor 99.97%
    Navitoclax (ABT-263) is a potent and orally active Bcl-2 family protein inhibitor that binds to multiple anti-apoptotic Bcl-2 family proteins, such as Bcl-xL, Bcl-2 and Bcl-w, with a Ki of less than 1 nM.
  • HY-100741
    S63845 Inhibitor 99.94%
    S63845 is a potent and selective myeloid cell leukemia 1 (MCL1) inhibitor with a Kd of 0.19 nM for human MCL1.
  • HY-50907
    ABT-737 Inhibitor 99.59%
    ABT-737 is a selective and BH3 mimetic Bcl-2, Bcl-xL and Bcl-w inhibitor with EC50s of 30.3 nM, 78.7 nM, and 197.8 nM, respectively.
  • HY-19741
    A-1331852 Inhibitor 99.81%
    A-1331852 is an orally available BCL-XL selective inhibitor with a Ki of less than 10 pM.
  • HY-114855
    BT2 Inhibitor 98.10%
    BT2 is a BCKDC kinase (BDK) inhibitor with an IC50 of 3.19 μM. BT2 binding to BDK triggers helix movements in the N-terminal domain, resulting in the dissociation of BDK from the branched-chain α-ketoacid dehydrogenase complex (BCKDC). BT2 (compound 4) is also a potent and selective Mcl-1 inhibitor with a Ki value of 59 μM.
  • HY-123054
    BTSA1 Activator
    BTSA1 is a potent, high affinity and orally active BAX activator with an IC50 of 250 nM and an EC50 of 144 nM. BTSA1 binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis.
  • HY-44432
    Navitoclax-piperazine Inhibitor
    Navitoclax-piperazine (ABT-263-piperazine) is a B-cell lymphoma extra large (BCL-XL) inhibitor. Navitoclax-piperazine and a VHL ligand for the E3 ubiquitin ligase can be used in the synthesis of PROTAC DT2216 (HY-130604).
  • HY-10969
    Obatoclax Mesylate Inhibitor 99.74%
    Obatoclax Mesylate (GX15-070 Mesylate) is an inhibitor of the BCL-2 family proteins. Obatoclax Mesylate (GX15-070 Mesylate) binds to BCL-2 with a Ki of 220 nM.
  • HY-101565
    AMG-176 Inhibitor 99.53%
    AMG-176 is a potent, selective and orally bioavailable MCL-1 inhibitor, with a Ki of 0.13 nM.
  • HY-19725
    A-1155463 Inhibitor 99.62%
    A-1155463 is a highly potent and selective BCL-XL inhibitor with an EC50 of 70 nM in Molt-4 cell.
  • HY-101533
    AZD-5991 Inhibitor 99.50%
    AZD-5991 is a potent and selective Mcl-1 inhibitor with an IC50 of 0.7 nM in FRET assay and a Kd of 0.17 nM in surface plasmon resonance (SPR) assay.
  • HY-15607A
    WEHI-539 hydrochloride Inhibitor 98.16%
    WEHI-539 hydrochloride is a selective inhibitor of Bcl-XL with an IC50 of 1.1 nM.
  • HY-12468
    A-1210477 Inhibitor 98.89%
    A-1210477 is a potent and selective inhibitor of MCL-1 with a Ki of 0.45 nM.
  • HY-12048
    Chelerythrine chloride Inhibitor >98.0%
    Chelerythrine (chloride) is a potent, cell-permeable inhibitor of protein kinase C, with an IC50 of 660 nM. Chelerythrine (chloride) inhibits the BclXL-Bak BH3 peptide binding with IC50 of 1.5 μM and displaces Bax from BclXL. Chelerythrine (chloride) induces apoptosis and autophagy.
  • HY-P0081
    Bax inhibitor peptide V5 Inhibitor 99.62%
    Bax inhibitor peptide V5 (BIP-V5) is a Bax-mediated apoptosis inhibitor, used for cancer treatment.
  • HY-N0087
    Gambogic Acid Inhibitor
    Gambogic Acid (Beta-Guttiferrin) is derived from the gamboges resin of the tree Garcinia hanburyi. Gambogic Acid (Beta-Guttiferrin) inhibits Bcl-XL, Bcl-2, Bcl-W, Bcl-B, Bfl-1 and Mcl-1 with IC50s of 1.47 μM, 1.21 μM, 2.02 μM, 0.66 μM, 1.06 μM and 0.79 μM.
  • HY-112218
    MIK665 Inhibitor 98.40%
    MIK665 (S-64315) is a special Mcl-1 inhibitor extracted from patent WO2016207225A1, compound Preparation 13, has an IC50 of 1.81 nM.
  • HY-117288
    S55746 Inhibitor 98.97%
    S55746 (BLC201) is a potent, orally active and selective BCL-2 inhibitor, with a Ki of 1.3 nM and a Kd of 3.9 nM. S55746 (BLC201) has antitumor activity with low toxicity.
  • HY-102027
    FX1 Inhibitor >98.0%
    FX1 is a potent and specific BCL6 inhibitor, with an IC50 of around 35 μM.

Bcl-2 family members have been grouped into three classes. The anti-apoptotic subfamily contains the Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B proteins, which suppress apoptosis and contain all four Bcl-2 homology domains, designated BH1-4. The pro-apoptotic subfamily contain BH1-3 domains, such as Bax, Bak, and Bok. A third class of BH3 only proteins Bad, Bid, Bim, Noxa and Puma have a conserved BH3 domain that can bind and regulate the anti-apoptotic BCL-2 proteins to promote apoptosis [1].


The intrinsic pathway is initiated by various signals, principally extracellular stimuli. BH3-only proteins (Bim, Bid, Bad, Noxa, Puma) engage with anti-apoptotic Bcl-2 family proteins to relieve their inhibition of Bax and Bak to activate them. Next, Bax and Bak are oligomerized and activated, leading to mitochondrial outer membrane permeabilization. Once mitochondrial membranes are permeabilized, cytochrome c and/or Smac/DIABLO is released into the cytoplasm, wherein they combine with an adaptor molecule, Apaf-1, and an inactive initiator Caspase, Pro-caspase 9, within a multiprotein complex called the apoptosome. Smac/DIABLO inhibits IAPs to activate Caspase 9. Caspase 9 activates Caspase 3, which is the initiation step for the cascade of Caspase activation. The extrinsic pathway can be activated by cell surface receptors, such as Fas and TNF Receptor, subsequently activating Caspase 8, and leads to Caspase 3 activation and cell demolition. Caspases in turn cleave a series of substrates, activate DNases and orchestrate the demolition of the cell. Bcl-2 family proteins are also found on the endoplasmic reticulum and the perinuclear membrane in hematopoietic cells, but they are predominantly localized to mitochondria [2]

 

Reference:
[1]. Cotter TG, et al. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer. 2009 Jul;9(7):501-7.

[2]. Kang MH, et al. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009 Feb 15;15(4):1126-32.

Targets/MCE-Bcl-2-Family-Signaling-Pathway.png

Bcl-2 family members have been grouped into three classes. The anti-apoptotic subfamily contains the Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B proteins, which suppress apoptosis and contain all four Bcl-2 homology domains, designated BH1-4. The pro-apoptotic subfamily contain BH1-3 domains, such as Bax, Bak, and Bok. A third class of BH3 only proteins Bad, Bid, Bim, Noxa and Puma have a conserved BH3 domain that can bind and regulate the anti-apoptotic BCL-2 proteins to promote apoptosis [1].


The intrinsic pathway is initiated by various signals, principally extracellular stimuli. BH3-only proteins (Bim, Bid, Bad, Noxa, Puma) engage with anti-apoptotic Bcl-2 family proteins to relieve their inhibition of Bax and Bak to activate them. Next, Bax and Bak are oligomerized and activated, leading to mitochondrial outer membrane permeabilization. Once mitochondrial membranes are permeabilized, cytochrome c and/or Smac/DIABLO is released into the cytoplasm, wherein they combine with an adaptor molecule, Apaf-1, and an inactive initiator Caspase, Pro-caspase 9, within a multiprotein complex called the apoptosome. Smac/DIABLO inhibits IAPs to activate Caspase 9. Caspase 9 activates Caspase 3, which is the initiation step for the cascade of Caspase activation. The extrinsic pathway can be activated by cell surface receptors, such as Fas and TNF Receptor, subsequently activating Caspase 8, and leads to Caspase 3 activation and cell demolition. Caspases in turn cleave a series of substrates, activate DNases and orchestrate the demolition of the cell. Bcl-2 family proteins are also found on the endoplasmic reticulum and the perinuclear membrane in hematopoietic cells, but they are predominantly localized to mitochondria [2]

 

Reference:
[1]. Cotter TG, et al. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer. 2009 Jul;9(7):501-7.

[2]. Kang MH, et al. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009 Feb 15;15(4):1126-32.

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