Target Information

Target General Information

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Target ID

T31309 (Former ID: TTDC00319)

Target Name

Apoptosis regulator Bcl-2 (BCL-2)

Synonyms

Bcl-2

Gene Name

BCL2

Target Type

Successful target

[1]

Disease

[+] 4 Target-related Diseases

Breast cancer [ICD-11: 2C60-2C6Y]

Mature B-cell leukaemia [ICD-11: 2A82]

Motor neuron disease [ICD-11: 8B60]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

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). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release. Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells.

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BioChemical Class

B-cell lymphoma Bcl-2

UniProt ID

BCL2_HUMAN

Sequence

MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPA
ASRDPVARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQLH
LTPFTARGRFATVVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMTEY
LNRHLHTWIQDNGGWDAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK

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3D Structure

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PDB

ADReCS ID

BADD_A05519 ; BADD_A06250 ; BADD_A06535 ; BADD_A08298

HIT2.0 ID

T71K92

Drugs and Modes of Action

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Approved Drug(s)

[+] 3 Approved Drugs

GDC-0199

Drug Info

Approved

Chronic lymphocytic leukaemia

[2]

MCI-186

Drug Info

Approved

Amyotrophic lateral sclerosis

[3]

Taxol

Drug Info

Approved

Solid tumour/cancer

[4]

Clinical Trial Drug(s)

[+] 18 Clinical Trial Drugs

ABT-263

Drug Info

Phase 3

Myelofibrosis

[5]

Oblimersen

Drug Info

Phase 3

Multiple myeloma

[6], [7]

RG7601

Drug Info

Phase 3

Chronic lymphocytic leukaemia

[8]

Taxol/Paraplatin/Herceptin

Drug Info

Phase 3

Breast cancer

[9]

Thymoquinone

Drug Info

Phase 2/3

Polycystic ovarian syndrome

[10]

Gossypol

Drug Info

Phase 2

Prostate cancer

[11], [12]

Obatoclax

Drug Info

Phase 2

Solid tumour/cancer

[13]

PI-88/Taxotere

Drug Info

Phase 2

Solid tumour/cancer

[14]

APG-1252

Drug Info

Phase 1/2

Small-cell lung cancer

[15]

APG-2575

Drug Info

Phase 1/2

Chronic lymphocytic leukaemia

[16]

AZD0466

Drug Info

Phase 1/2

Hematologic tumour

[17]

AI-850

Drug Info

Phase 1

Solid tumour/cancer

[18], [19]

BCL201

Drug Info

Phase 1

Follicular lymphoma

[20]

BGB-11417

Drug Info

Phase 1

Acute myeloid leukaemia

[21]

Irofulven/Taxotere

Drug Info

Phase 1

Solid tumour/cancer

[22]

LP-108

Drug Info

Phase 1

Acute myeloid leukaemia

[23]

Pc4

Drug Info

Phase 1

Psoriasis vulgaris

[24]

VOB560

Drug Info

Phase 1

Multiple myeloma

[25]

Mode of Action

[+] 5 Modes of Action

Modulator

[+] 9 Modulator drugs

GDC-0199

Drug Info

[26]

Taxol

Drug Info

[19]

RG7601

Drug Info

[26]

Taxol/Paraplatin/Herceptin

Drug Info

[31]

PI-88/Taxotere

Drug Info

[34]

AI-850

Drug Info

[18], [19]

Irofulven/Taxotere

Drug Info

[39]

modified HA14-1 compounds (cancer)

Drug Info

[48]

WL-276

Drug Info

[49]

Regulator (upregulator)

[+] 1 Regulator (upregulator) drugs

MCI-186

Drug Info

[1]

Inhibitor

[+] 23 Inhibitor drugs

ABT-263

Drug Info

[27], [28], [29]

Oblimersen

Drug Info

[30]

Thymoquinone

Drug Info

[32]

Obatoclax

Drug Info

[13]

APG-1252

Drug Info

[35]

APG-2575

Drug Info

[36]

AZD0466

Drug Info

[37]

BCL201

Drug Info

[20]

BGB-11417

Drug Info

[38]

VOB560

Drug Info

[41]

Indole-based analog 2

Drug Info

[42]

Indole-based analog 3

Drug Info

[42]

PMID27744724-Compound-10

Drug Info

[42]

PMID27744724-Compound-18

Drug Info

[42]

PMID27744724-Compound-21

Drug Info

[42]

ABT-737

Drug Info

[43]

2,3,4-trihydroxy-5-isopropyl-N-phenyl-benzamide

Drug Info

[44]

4,5-dibenzylbenzene-1,2-diol

Drug Info

[45]

5,10-Dioxy-2-phenyl-benzo[g]pteridin-4-ylamine

Drug Info

[46]

Apogossypol

Drug Info

[47]

N-phenyl-2,3,4-trihydroxy-5-benzyl-benzamide

Drug Info

[44]

QEDIIRNIARHLAQVGDSMDR

Drug Info

[44]

TW-37

Drug Info

[44]

Regulator

[+] 1 Regulator drugs

Gossypol

Drug Info

[33]

Agonist

[+] 1 Agonist drugs

Pc4

Drug Info

[24]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 20 KEGG Pathways	+
1	NF-kappa B signaling pathway
2	HIF-1 signaling pathway
3	Sphingolipid signaling pathway
4	Protein processing in endoplasmic reticulum
5	PI3K-Akt signaling pathway
6	Apoptosis
7	Adrenergic signaling in cardiomyocytes
8	Focal adhesion
9	Neurotrophin signaling pathway
10	Cholinergic synapse
11	Amyotrophic lateral sclerosis (ALS)
12	Toxoplasmosis
13	Tuberculosis
14	Hepatitis B
15	Epstein-Barr virus infection
16	Pathways in cancer
17	MicroRNAs in cancer
18	Colorectal cancer
19	Prostate cancer
20	Small cell lung cancer
NetPath Pathway	[+] 7 NetPath Pathways	+
1	IL5 Signaling Pathway
2	TCR Signaling Pathway
3	IL2 Signaling Pathway
4	IL3 Signaling Pathway
5	Leptin Signaling Pathway
6	RANKL Signaling Pathway
7	TSLP Signaling Pathway
Panther Pathway	[+] 3 Panther Pathways	+
1	Apoptosis signaling pathway
2	Oxidative stress response
3	CCKR signaling map ST
PID Pathway	[+] 14 PID Pathways	+
1	Role of Calcineurin-dependent NFAT signaling in lymphocytes
2	IL2-mediated signaling events
3	IL2 signaling events mediated by PI3K
4	Ceramide signaling pathway
5	Direct p53 effectors
6	RXR and RAR heterodimerization with other nuclear receptor
7	ATF-2 transcription factor network
8	C-MYB transcription factor network
9	HIV-1 Nef: Negative effector of Fas and TNF-alpha
10	Caspase Cascade in Apoptosis
11	Signaling events mediated by Stem cell factor receptor (c-Kit)
12	EPO signaling pathway
13	IL2 signaling events mediated by STAT5
14	Validated targets of C-MYC transcriptional repression
Reactome	[+] 3 Reactome Pathways	+
1	Activation of BAD and translocation to mitochondria
2	BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members
3	The NLRP1 inflammasome
WikiPathways	[+] 25 WikiPathways	+
1	DNA Damage Response (only ATM dependent)
2	Senescence and Autophagy in Cancer
3	IL-2 Signaling Pathway
4	FAS pathway and Stress induction of HSP regulation
5	Focal Adhesion
6	Kit receptor signaling pathway
7	IL-3 Signaling Pathway
8	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
9	Apoptosis
10	Nanoparticle triggered autophagic cell death
11	Amyotrophic lateral sclerosis (ALS)
12	Integrated Pancreatic Cancer Pathway
13	Corticotropin-releasing hormone
14	Interleukin-11 Signaling Pathway
15	Prostate Cancer
16	miR-targeted genes in muscle cell - TarBase
17	miR-targeted genes in lymphocytes - TarBase
18	miR-targeted genes in leukocytes - TarBase
19	Integrated Breast Cancer Pathway
20	Integrated Cancer pathway
21	Intrinsic Pathway for Apoptosis
22	Apoptosis Modulation and Signaling
23	TP53 Network
24	Influenza A virus infection
25	IL-5 Signaling Pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

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 2

2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.

REF 3

2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

ClinicalTrials.gov (NCT04472598) Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis (TRANSFORM-1). U.S. National Institutes of Health.

REF 6

URL: 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 7

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 8

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 9

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 10

ClinicalTrials.gov (NCT04852510) Amelioration of Polycystic Ovary Syndrome Related Disorders by Supplementation of Thymoquinone and Metformin. U.S. National Institutes of Health.

REF 11

REF 12

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 13

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 14

ClinicalTrials.gov (NCT00268593) Pilot Efficacy Study of PI-88 With Docetaxel to Treat Prostate Cancer. U.S. National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT04210037) Study of APG-1252 Plus Paclitaxel in Patients With Relapsed/Refractory Small Cell Lung Cancer. U.S. National Institutes of Health.

REF 16

ClinicalTrials.gov (NCT04494503) Study of APG2575 Single Agent and Combination Therapy in Patients With Relapsed/Refractory CLL/SLL. U.S. National Institutes of Health.

REF 17

ClinicalTrials.gov (NCT04865419) Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies. U.S. National Institutes of Health.

REF 18

Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850). Pharm Res. 2005 Mar;22(3):347-55.

REF 19

Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.

REF 20

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 21

ClinicalTrials.gov (NCT04771130) A Study of BGB-11417 in Participants With Myeloid Malignancies. U.S. National Institutes of Health.

REF 22

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 23

ClinicalTrials.gov (NCT04139434) Dose-escalation Study of Oral Administration of LP-108 in Patients With Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML). U.S. National Institutes of Health.

REF 24

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 25

ClinicalTrials.gov (NCT04702425) VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma). U.S. National Institutes of Health.

REF 26

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.

REF 27

Clinical pipeline report, company report or official report of Roche (2009).

REF 28

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 29

ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8.

REF 30

Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.

REF 31

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 32

Apoptosis as a mechanism for the treatment of adult T cell leukemia: promising drugs from benchside to bedside. Drug Discov Today. 2020 Jul;25(7):1189-1197.

REF 33

Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.

REF 34

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 35

Bcl-2/Bcl-xl inhibitor APG-1252-M1 is a promising therapeutic strategy for gastric carcinoma. Cancer Med. 2020 Jun;9(12):4197-4206.

REF 36

A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma. Oncol Res. 2020 Sep 1;28(4):331-344.

REF 37

Design and optimisation of dendrimer-conjugated Bcl-2/x L inhibitor, AZD0466, with improved therapeutic index for cancer therapy. Commun Biol. 2021 Jan 25;4(1):112.

REF 38

Clinical pipeline report, company report or official report of BeiGene.

REF 39

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 40

National Cancer Institute Drug Dictionary (drug name LP-108).

REF 41

Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer. Cells. 2020 May 21;9(5):1287.

REF 42

Mcl-1 inhibitors: a patent review.Expert Opin Ther Pat. 2017 Feb;27(2):163-178.

REF 43

Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem. 2007 Feb 22;50(4):641-62.

REF 44

Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem. 2006 Oct 19;49(21):6139-42.

REF 45

Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention. J Med Chem. 2010 May 27;53(10):3899-906.

REF 46

Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J Med Chem. 2001 Dec 6;44(25):4313-24.

REF 47

REF 48

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 49

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.

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