Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJGNVC)

• DTT Name: Apoptosis regulator Bcl-2 (BCL-2)
• Synonyms: Bcl-2
• Gene Name: BCL2
• DTT Type: Successful target; [1]
• BioChemical Class: B-cell lymphoma Bcl-2
• UniProt ID: BCL2_HUMAN
• TTD ID: T31309
• Sequence:
  MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPA
  ASRDPVARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQLH
  LTPFTARGRFATVVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMTEY
  LNRHLHTWIQDNGGWDAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK
• 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.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  HIF-1 signaling pathway (hsa04066)
  Sphingolipid signaling pathway (hsa04071)
  Protein processing in endoplasmic reticulum (hsa04141)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Focal adhesion (hsa04510)
  Neurotrophin signaling pathway (hsa04722)
  Cholinergic synapse (hsa04725)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  MicroRNAs in cancer (hsa05206)
  Colorectal cancer (hsa05210)
  Prostate cancer (hsa05215)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members (R-HSA-111453)
  The NLRP1 inflammasome (R-HSA-844455)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GDC-0199	DMH0QKA	Chronic lymphocytic leukaemia	2A82.0	Approved	[2]
MCI-186	DM8ZHP1	Amyotrophic lateral sclerosis	8B60.0	Approved	[1]
Taxol	DMUOT9V	Breast cancer	2C60-2C65	Approved	[3]

18 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-263	DMNE56X	Myelofibrosis	2A20.2	Phase 3	[4]
Oblimersen	DM7KI4E	Melanoma	2C30	Phase 3	[5]
RG7601	DMDVAFP	Chronic lymphocytic leukaemia	2A82.0	Phase 3	[2]
Taxol/Paraplatin/Herceptin	DML6GAN	Breast cancer	2C60-2C65	Phase 3	[6]
Thymoquinone	DMVDTR2	Polycystic ovarian syndrome	5A80.1	Phase 2/3	[7]
Gossypol	DMJWE3I	Prostate cancer	2C82.0	Phase 2	[8]
Obatoclax	DMPF9ZM	Solid tumour/cancer	2A00-2F9Z	Phase 2	[9]
PI-88/Taxotere	DM4FIWC	Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]
APG-1252	DM8O3R9	Small-cell lung cancer	2C25.Y	Phase 1/2	[11]
APG-2575	DMPWBM2	Chronic lymphocytic leukaemia	2A82.0	Phase 1/2	[12]
AZD0466	DMWLZI6	Hematologic tumour	2B33.Y	Phase 1/2	[13]
AI-850	DMDA1UB	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
BCL201	DMZ51EX	Follicular lymphoma	2A80	Phase 1	[15]
BGB-11417	DM7QTIC	Acute myeloid leukaemia	2A60	Phase 1	[16]
LOXO-338	DMPX2ZR	Haematological malignancy	2B33.Y	Phase 1	[17]
LP-108	DMYIXQZ	Acute myeloid leukaemia	2A60	Phase 1	[18]
Pc4	DM23K45	Psoriasis vulgaris	EA90	Phase 1	[19]
VOB560	DMDG30Q	Acute myeloid leukaemia	2A60	Phase 1	[20]

5 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Indole-based analog 2	DM0NEVC	N. A.	N. A.	Patented	[21]
Indole-based analog 3	DMTEYQJ	N. A.	N. A.	Patented	[21]
PMID27744724-Compound-10	DMFKS2P	N. A.	N. A.	Patented	[21]
PMID27744724-Compound-18	DM73S2C	N. A.	N. A.	Patented	[21]
PMID27744724-Compound-21	DM18UA5	N. A.	N. A.	Patented	[21]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-737	DML0DBV	N. A.	N. A.	Terminated	[22]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2,3,4-trihydroxy-5-isopropyl-N-phenyl-benzamide	DMCAZ32	Discovery agent	N.A.	Investigative	[23]
4,5-dibenzylbenzene-1,2-diol	DMHURXY	Discovery agent	N.A.	Investigative	[24]
5,10-Dioxy-2-phenyl-benzo[g]pteridin-4-ylamine	DMM7N6K	Discovery agent	N.A.	Investigative	[25]
Apogossypol	DM7OPCH	Solid tumour/cancer	2A00-2F9Z	Investigative	[26]
modified HA14-1 compounds (cancer)	DMB5OG8	Discovery agent	N.A.	Investigative	[27]
N-phenyl-2,3,4-trihydroxy-5-benzyl-benzamide	DM0JI2L	Discovery agent	N.A.	Investigative	[23]
QEDIIRNIARHLAQVGDSMDR	DMJ38YV	Discovery agent	N.A.	Investigative	[23]
TW-37	DMDE8YS	Discovery agent	N.A.	Investigative	[23]
WL-276	DM8SEHO	Solid tumour/cancer	2A00-2F9Z	Investigative	[28]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	5.22E-01	0.04	0.19
Breast cancer	2C82	Breast tissue	1.08E-24	-0.23	-0.74
Prostate cancer	2C82	Prostate	1.29E-02	0.16	0.62
Lung cancer	2C82	Lung tissue	9.45E-01	1.35E-02	0.05
Lateral sclerosis	8A00.0	Cervical spinal cord	2.52E-02	0.17	0.72

References

• [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.
• [2] ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8.
• [3] Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
• [4] Clinical pipeline report, company report or official report of Roche (2009).
• [5] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [6] 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.
• [7] 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.
• [8] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [9] 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.
• [10] 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.
• [11] Bcl-2/Bcl-xl inhibitor APG-1252-M1 is a promising therapeutic strategy for gastric carcinoma. Cancer Med. 2020 Jun;9(12):4197-4206.
• [12] 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.
• [13] 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.
• [14] Intravenous hydrophobic drug delivery: a porous particle formulation of paclitaxel (AI-850). Pharm Res. 2005 Mar;22(3):347-55.
• [15] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [16] Clinical pipeline report, company report or official report of BeiGene.
• [17] ClinicalTrials.gov (NCT05024045) A Phase 1 Study of Oral LOXO-338, a Selective BCL-2 Inhibitor, in Patients With Advanced Hematologic Malignancies. U.S.National Institutes of Health.
• [18] National Cancer Institute Drug Dictionary (drug name LP-108).
• [19] 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.
• [20] Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer. Cells. 2020 May 21;9(5):1287.
• [21] Mcl-1 inhibitors: a patent review.Expert Opin Ther Pat. 2017 Feb;27(2):163-178.
• [22] Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem. 2007 Feb 22;50(4):641-62.
• [23] Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem. 2006 Oct 19;49(21):6139-42.
• [24] Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention. J Med Chem. 2010 May 27;53(10):3899-906.
• [25] Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J Med Chem. 2001 Dec 6;44(25):4313-24.
• [26] 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: 7920).
• [27] 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.
• [28] 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.