Target Information

Target General Infomation
Target ID
T31309
Former ID
TTDC00319
Target Name
Apoptosis regulator Bcl-2
Gene Name
BCL2
Synonyms
Bcl-2; BCL2
Target Type
Successful
Disease Advanced small cell lung cancer; Relapsed or refractory chronic lymphocytic leukemia; Lymphoid malignancies [ICD9: 140-229, 140-239, 162, 162.9, 202, 204.0, 204.1, 208.9; ICD10: C33-C34, C34.90, C81-C86, C91-C95, C91.0, C91.1]
Advanced melanoma; Multiple myeloma [ICD9: 172, 203.0; ICD10: C43, C90]
Amyotrophic lateral sclerosis [ICD9: 335.2; ICD10: G12.2]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Chronic lymphocytic leukaemia [ICD10: C91]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Prostate cancer [ICD9: 185; ICD10: C61]
Psoriasis [ICD9: 696; ICD10: L40]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Unspecified [ICD code not available]
Function
Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).
BioChemical Class
Bcl-2 family
Target Validation
T31309
UniProt ID
P10415
Sequence
MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPA
ASRDPVARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQLH
LTPFTARGRFATVVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMTEY
LNRHLHTWIQDNGGWDAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK
Drugs and Mode of Action
Drug(s) GDC-0199 Drug Info Approved Chronic lymphocytic leukaemia [889440]
MCI-186 Drug Info Approved Amyotrophic lateral sclerosis [889446]
Oral paclitaxel Drug Info Approved Cancer [551871]
Taxol Drug Info Approved Breast carcinoma [530307]
GDC-0199 Drug Info Phase 3 Cancer [524916], [543069]
Liposomal encapsulated paclitaxel (LEP) Drug Info Phase 3 Cancer [551035]
Oblimersen Drug Info Phase 3 Advanced melanoma; Multiple myeloma [521495], [543024]
RG7601 Drug Info Phase 3 Chronic lymphocytic leukaemia [549281]
Taxol/Paraplatin/Herceptin Drug Info Phase 3 Breast cancer [528260]
ABT-263 Drug Info Phase 2 Advanced small cell lung cancer; Relapsed or refractory chronic lymphocytic leukemia; Lymphoid malignancies [543070], [551607]
Gossypol Drug Info Phase 2 Prostate cancer [467538], [522588]
Obatoclax Drug Info Phase 2 Solid tumours [531104]
PI-88/Taxotere Drug Info Phase 2 Cancer [521777]
AI-850 Drug Info Phase 1 Solid tumours [527516], [530307]
Irofulven/Taxotere Drug Info Phase 1 Cancer [551729]
Pc4 (topical formulation Drug Info Phase 1 Psoriasis [526695]
ABT-737 Drug Info Terminated Discovery agent [543071], [546653]
Inhibitor 2,3,4-trihydroxy-5-isopropyl-N-phenyl-benzamide Drug Info [528469]
4,5-dibenzylbenzene-1,2-diol Drug Info [530890]
5,10-Dioxy-2-phenyl-benzo[g]pteridin-4-ylamine Drug Info [526209]
ABT-263 Drug Info [536702], [536883], [551607]
ABT-737 Drug Info [528642]
Apogossypol Drug Info [542839]
N-phenyl-2,3,4-trihydroxy-5-benzyl-benzamide Drug Info [528469]
Obatoclax Drug Info [531104]
Oblimersen Drug Info [537114]
QEDIIRNIARHLAQVGDSMDR Drug Info [528469]
TW-37 Drug Info [528469]
Modulator AI-850 Drug Info [527516], [530307]
GDC-0199 Drug Info [532178]
Irofulven/Taxotere Drug Info [526976]
Liposomal encapsulated paclitaxel (LEP) Drug Info [526031], [530307]
modified HA14-1 compounds (cancer), GL Pharmaceuticals Drug Info [527372]
Oral paclitaxel Drug Info [526031], [530307]
PI-88/Taxotere Drug Info [530520]
RG7601 Drug Info [532178]
Taxol Drug Info [530307]
Taxol/Paraplatin/Herceptin Drug Info [527947]
WL-276 Drug Info [529510]
Regulator Gossypol Drug Info [536135]
Regulator (upregulator) MCI-186 Drug Info [536447]
Agonist Pc4 (topical formulation Drug Info [526695]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway NF-kappa B signaling pathway
HIF-1 signaling pathway
Sphingolipid signaling pathway
Protein processing in endoplasmic reticulum
PI3K-Akt signaling pathway
Apoptosis
Adrenergic signaling in cardiomyocytes
Focal adhesion
Neurotrophin signaling pathway
Cholinergic synapse
Amyotrophic lateral sclerosis (ALS)
Toxoplasmosis
Tuberculosis
Hepatitis B
Epstein-Barr virus infection
Pathways in cancer
MicroRNAs in cancer
Colorectal cancer
Prostate cancer
Small cell lung cancer
NetPath Pathway IL5 Signaling Pathway
TCR Signaling Pathway
IL2 Signaling Pathway
IL3 Signaling Pathway
Leptin Signaling Pathway
RANKL Signaling Pathway
TSLP Signaling Pathway
PANTHER Pathway Apoptosis signaling pathway
Oxidative stress response
CCKR signaling map ST
Pathway Interaction Database Role of Calcineurin-dependent NFAT signaling in lymphocytes
IL2-mediated signaling events
IL2 signaling events mediated by PI3K
Ceramide signaling pathway
Direct p53 effectors
RXR and RAR heterodimerization with other nuclear receptor
ATF-2 transcription factor network
C-MYB transcription factor network
Negative effector of Fas and TNF-alpha
Caspase Cascade in Apoptosis
Signaling events mediated by Stem cell factor receptor (c-Kit)
EPO signaling pathway
IL2 signaling events mediated by STAT5
Validated targets of C-MYC transcriptional repression
Reactome Activation of BAD and translocation to mitochondria
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members
The NLRP1 inflammasome
WikiPathways DNA Damage Response (only ATM dependent)
Senescence and Autophagy in Cancer
IL-2 Signaling Pathway
FAS pathway and Stress induction of HSP regulation
Focal Adhesion
Kit receptor signaling pathway
IL-3 Signaling Pathway
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
Apoptosis
Nanoparticle triggered autophagic cell death
Amyotrophic lateral sclerosis (ALS)
Integrated Pancreatic Cancer Pathway
Corticotropin-releasing hormone
Interleukin-11 Signaling Pathway
Prostate Cancer
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in leukocytes - TarBase
Integrated Breast Cancer Pathway
Integrated Cancer pathway
Intrinsic Pathway for Apoptosis
Apoptosis Modulation and Signaling
TP53 Network
Influenza A virus infection
IL-5 Signaling Pathway
References
Ref 467538(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4204).
Ref 521495ClinicalTrials.gov (NCT00024440) Fludarabine and Cyclophosphamide With or Without Oblimersen in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. U.S. National Institutes ofHealth.
Ref 521777ClinicalTrials.gov (NCT00268593) Pilot Efficacy Study of PI-88 With Docetaxel to Treat Prostate Cancer. U.S. National Institutes of Health.
Ref 522588ClinicalTrials.gov (NCT00848016) Gossypol Acetic Acid in Treating Patients With Recurrent, Metastatic, or Primary Adrenocortical Cancer That Cannot Be Removed By Surgery. U.S. National Institutes of Health.
Ref 524916ClinicalTrials.gov (NCT02242942) A Study to Compare the Efficacy and Safety of Obinutuzumab + GDC-0199 Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia. U.S. National Institutes of Health.
Ref 526695Association between the photodynamic loss of Bcl-2 and the sensitivity to apoptosis caused by phthalocyanine photodynamic therapy. Photochem Photobiol. 2003 Jul;78(1):1-8.
Ref 527516Pharm Res. 2005 Mar;22(3):347-55.Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850).
Ref 528260Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92.
Ref 530307Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
Ref 531104Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leuk. 2010 Aug;10(4):285-9.
Ref 543024(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8269).
Ref 543069(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8318).
Ref 543070(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8319).
Ref 543071(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8320).
Ref 546653Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009496)
Ref 549281Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034622)
Ref 551035Clinical pipeline report, company report or official report of Insys Therapeutics.
Ref 551607Clinical pipeline report, company report or official report of Roche (2009).
Ref 551729MGI PHARMA Initiates Drug Combination Trial of Irofulven and Taxotere in Patients With Advanced Cancers; Phase 1 Dose-Escalating Trial to Evaluate Novel Combination Therapy. 2001 Business Wire
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 8894402016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. doi: 10.1038/nrd.2017.14.
Ref 889446Drugs@FDA (Edaravone)
Ref 526031The binding conformation of Taxol in beta-tubulin: a model based on electron crystallographic density. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5312-6. Epub 2001 Apr 17.
Ref 526209J Med Chem. 2001 Dec 6;44(25):4313-24.Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening.
Ref 526695Association between the photodynamic loss of Bcl-2 and the sensitivity to apoptosis caused by phthalocyanine photodynamic therapy. Photochem Photobiol. 2003 Jul;78(1):1-8.
Ref 526976Antitumor activity of irofulven monotherapy and in combination with mitoxantrone or docetaxel against human prostate cancer models. Prostate. 2004 Apr 1;59(1):22-32.
Ref 527372The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. Mol Cancer Ther. 2004 Dec;3(12):1513-24.
Ref 527516Pharm Res. 2005 Mar;22(3):347-55.Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850).
Ref 527947Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32.
Ref 528469J Med Chem. 2006 Oct 19;49(21):6139-42.Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Ref 528642J Med Chem. 2007 Feb 22;50(4):641-62. Epub 2007 Jan 26.Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
Ref 529510WL-276, an antagonist against Bcl-2 proteins, overcomes drug resistance and suppresses prostate tumor growth. Cancer Res. 2008 Jun 1;68(11):4377-83.
Ref 530307Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
Ref 530520Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer. Ann Oncol. 2010 Jun;21(6):1302-7.
Ref 530890J Med Chem. 2010 May 27;53(10):3899-906.Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention.
Ref 531104Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leuk. 2010 Aug;10(4):285-9.
Ref 532178ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.
Ref 536135Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
Ref 536447Emerging disease-modifying therapies for the treatment of motor neuron disease/amyotropic lateral sclerosis. Expert Opin Emerg Drugs. 2007 May;12(2):229-52.
Ref 536702ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8.
Ref 536883ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2008 Oct;7(10):3265-74.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 542839(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7920).
Ref 551607Clinical pipeline report, company report or official report of Roche (2009).

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