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BCL2 apoptosis regulator

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Target id: 2844

Nomenclature: BCL2 apoptosis regulator

Abbreviated Name: Bcl-2

Family: B-cell lymphoma 2 (Bcl-2) protein family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 239 18q21.33 BCL2 BCL2 apoptosis regulator
Mouse 1 236 1 49.76 cM Bcl2 B cell leukemia/lymphoma 2
Rat 1 236 13p11 Bcl2 BCL2, apoptosis regulator
Previous and Unofficial Names Click here for help
B-cell CLL/lymphoma 2 | BCL2, apoptosis regulator | BCL2
Database Links Click here for help
Alphafold P10415 (Hs), P10417 (Mm), P49950 (Rn)
ChEMBL Target CHEMBL4860 (Hs), CHEMBL3309111 (Mm)
DrugBank Target P10415 (Hs)
Ensembl Gene ENSG00000171791 (Hs), ENSMUSG00000057329 (Mm), ENSRNOG00000067693 (Rn), ENSRNOG00000002791 (Rn)
Entrez Gene 596 (Hs), 12043 (Mm), 24224 (Rn)
Human Protein Atlas ENSG00000171791 (Hs)
KEGG Gene hsa:596 (Hs), mmu:12043 (Mm), rno:24224 (Rn)
OMIM 151430 (Hs)
Pharos P10415 (Hs)
RefSeq Nucleotide NM_000633 (Hs), NM_009741 (Mm), NM_016993 (Rn)
RefSeq Protein NP_000624 (Hs), NP_033871 (Mm), NP_058689 (Rn)
SynPHARM 81962 (in complex with navitoclax)
UniProtKB P10415 (Hs), P10417 (Mm), P49950 (Rn)
Wikipedia BCL2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Bcl_2-Navitoclax (ABT-263) Complex.
PDB Id:  4LVT
Ligand:  navitoclax
Resolution:  2.05Å
Species:  Human
References:  14

Download all structure-activity data for this target as a CSV file go icon to follow link

Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
venetoclax Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist >11.0 pKi 5,14
⤷ pKi >11.0 (Ki <1x10-11 M) [5,14]
Description: Note that this Ki is below the detection limit of the assay.
lisaftoclax Small molecule or natural product Click here for species-specific activity table Hs Antagonist >10.0 pKi 10
⤷ pKi >10.0 (Ki <1x10-10 M) [10]
APG-1252-M1 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.4 pKi 9
⤷ pKi 9.4 (Ki 4.5x10-10 M) [9]
navitoclax Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist >9.0 pKi 13
⤷ pKi >9.0 (Ki <1x10-9 M) [13]
ABT-737 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist >9.0 pKi 2
⤷ pKi >9.0 (Ki <1x10-9 M) [2]
obatoclax Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.0 pKi 16
⤷ pKi 6.0 (Ki 1.1x10-6 M) [16]
Description: In vitro antagonism determined in a fluorescence polarisation assay.
sonrotoclax Small molecule or natural product Hs Antagonist 9.5 – 10.7 pIC50 7
⤷ pIC50 10.7 (IC50 1.9x10-11 M) [7]
Description: Potency vs. wild type hBCL2 determined in a biochemical assay
pIC50 9.5 (IC50 3.4x10-10 M) [7]
Description: Potency vs. hBCL2G101V determined in a biochemical assay
AZD4320 Small molecule or natural product Click here for species-specific activity table Hs Antagonist >9.5 pIC50 4
⤷ pIC50 >9.5 (IC50 <3x10-10 M) [4]
Immunopharmacology Comments
The role of Bcl-2 family members in immunity and disease is reviewed in [6]. Pharmacological inhibition of Bcl-2 family proteins reduces disease severity in several animal models of autoimmunity; see ligand ABT-737 [1].
Immuno Process Associations
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  T cell (activation)
Immuno Process:  Immune system development
General Comments
Bcl-2 is an anti-apoptotic (prosurvival) protein with oncogenic actions which was originally identified in chromosomal translocations in follicular lymphoma cells [15]. Abnormal expression of Bcl-2 de-stabilises the balance between pro- and anti-apoptotic signals, driving the homeostatic balance between cell growth and cell death towards growth. The role of Bcl-2 in cancers and other important conditions (for example autoimmune diseases and schizophrenia) makes it an attractive target for pharmaceutical intervention. The first Bcl-2 antagonist to be approved for clinical use is venetoclax (ABT-199) [5]. Another small molecule inhibitor, navitoclax (ABT-263) [13], is in also developement for chronic lymphocytic leukemia (CLL) and other blood cancers. A Bcl-2 antinsense oligonucleotide was assessed in lymphoma [3,11] and ABT-737 [8,12] was investigated as a breast and ovarian cancer therapy.

References

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1. Bardwell PD, Gu J, McCarthy D, Wallace C, Bryant S, Goess C, Mathieu S, Grinnell C, Erickson J, Rosenberg SH et al.. (2009) The Bcl-2 family antagonist ABT-737 significantly inhibits multiple animal models of autoimmunity. J Immunol, 182 (12): 7482-9. [PMID:19494271]

2. Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC et al.. (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem, 50 (4): 641-62. [PMID:17256834]

3. Dias N, Stein CA. (2002) Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm, 54 (3): 263-9. [PMID:12445555]

4. Diebold RB, Gero TW, Grover P, Huang S, Ioannidis S, Ogoe CA, Saeh JC. (2016) Chemical compounds. Patent number: US9248140B2. Assignee: AstraZeneca AB. Priority date: 06/08/2010. Publication date: 02/02/2016.

5. Doherty GA, Elmore SW, Hasvold LA, Souers AJ, Tao Z-F, Wang GT, Wang L, Mantei R, Hansen TM. (2013) Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases. Patent number: US8580794. Assignee: Abbvie Inc.. Priority date: 26/05/2009. Publication date: 12/11/2013.

6. Droin NM, Green DR. (2004) Role of Bcl-2 family members in immunity and disease. Biochim Biophys Acta, 1644 (2-3): 179-88. [PMID:14996502]

7. Guo Y, Xue H, Hu N, Liu Y, Sun H, Yu D, Qin L, Shi G, Wang F, Xin L et al.. (2024) Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2. J Med Chem, 67 (10): 7836-7858. [PMID:38695063]

8. Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, Hosui A, Miyagi T, Tatsumi T, Ishida H et al.. (2010) The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology, 52 (4): 1310-21. [PMID:20799354]

9. Hopkins J, Tsuruda P, Chapman C, Sweigard H, Poon Y, Marquess D, David N, Dananberd J, Laberg RM. (2019) Treatment of ophthalmic conditions such as macular degeneration, glaucoma, and diabetic retinopathy using pharmaceutical agents that eliminate senescent cells. Patent number: WO2019033119A1. Assignee: Unity Biotechnology, Inc., Buck Institute For Research On Aging. Priority date: 13/08/2018. Publication date: 14/02/2019.

10. Luo Q, Pan W, Zhou S, Wang G, Yi H, Zhang L, Yan X, Yuan L, Liu Z, Wang J et al.. (2020) A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma. Oncol Res, 28 (4): 331-344. [PMID:32093809]

11. Mavromatis BH, Cheson BD. (2004) Novel therapies for chronic lymphocytic leukemia. Blood Rev, 18 (2): 137-48. [PMID:15010151]

12. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ et al.. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 435 (7042): 677-81. [PMID:15902208]

13. Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X et al.. (2008) Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem, 51 (21): 6902-15. [PMID:18841882]

14. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ et al.. (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med, 19 (2): 202-8. [PMID:23291630]

15. Vaux DL, Cory S, Adams JM. (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature, 335 (6189): 440-2. [PMID:3262202]

16. Wan Y, Dai N, Tang Z, Fang H. (2018) Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents. Eur J Med Chem, 146: 471-482. [PMID:29407973]

How to cite this page

B-cell lymphoma 2 (Bcl-2) protein family: BCL2 apoptosis regulator. Last modified on 06/05/2024. Accessed on 11/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2844.