TTD | Target: T31309

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 melanoma; Multiple myeloma [ICD9: 172, 203.0; ICD10: C43, C90]
	Amyotrophic lateral sclerosis [ICD9: 335.2; ICD10: G12.2]
	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]
	Breast cancer [ICD9: 174, 175; ICD10: C50]
	Cancer [ICD9: 140-229; ICD10: C00-C96]
	Chronic lymphocytic leukaemia [ICD10: C91]
	Psoriasis [ICD9: 696; ICD10: L40]
	Prostate cancer [ICD9: 185; ICD10: C61]
	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 521495	ClinicalTrials.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 521777	ClinicalTrials.gov (NCT00268593) Pilot Efficacy Study of PI-88 With Docetaxel to Treat Prostate Cancer. U.S. National Institutes of Health.
Ref 522588	ClinicalTrials.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 524916	ClinicalTrials.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 526695	Association 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 527516	Pharm Res. 2005 Mar;22(3):347-55.Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850).
Ref 528260	Randomized 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 530307	Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
Ref 531104	Phase 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 546653	Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009496)
Ref 549281	Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034622)
Ref 551035	Clinical pipeline report, company report or official report of Insys Therapeutics.
Ref 551607	Clinical pipeline report, company report or official report of Roche (2009).
Ref 551729	MGI 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 551871	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 889440	2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. doi: 10.1038/nrd.2017.14.
Ref 889446	Drugs@FDA (Edaravone)
Ref 526031	The 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 526209	J Med Chem. 2001 Dec 6;44(25):4313-24.Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening.
Ref 526695	Association 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 526976	Antitumor 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 527372	The 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 527516	Pharm Res. 2005 Mar;22(3):347-55.Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850).
Ref 527947	Two 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 528469	J Med Chem. 2006 Oct 19;49(21):6139-42.Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
Ref 528642	J 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 529510	WL-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 530307	Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
Ref 530520	Multicentre 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 530890	J Med Chem. 2010 May 27;53(10):3899-906.Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention.
Ref 531104	Phase 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 532178	ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.
Ref 536135	Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
Ref 536447	Emerging disease-modifying therapies for the treatment of motor neuron disease/amyotropic lateral sclerosis. Expert Opin Emerg Drugs. 2007 May;12(2):229-52.
Ref 536702	ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8.
Ref 536883	ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2008 Oct;7(10):3265-74.
Ref 537114	Emerging 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 551607	Clinical pipeline report, company report or official report of Roche (2009).

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Target Information

Prof. Feng ZHU

Prof. Yuzong CHEN