Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTU1E82)

• DTT Name: Apoptosis regulator Bcl-xL (BCL-xL)
• Synonyms: Bcl2like protein 1; Bcl2L1; Bcl2-L-1; Bcl-XL; Bcl-2-like protein 1; BCLX; BCL2L; Apoptosis regulator Bcl-X
• Gene Name: BCL2L1
• DTT Type: Clinical trial target; [1]
• Related Disease: Myeloproliferative neoplasm [ICD-11: 2A20]
• BioChemical Class: B-cell lymphoma Bcl-2
• UniProt ID: B2CL1_HUMAN
• TTD ID: T56510
• Sequence:
  MSQSNRELVVDFLSYKLSQKGYSWSQFSDVEENRTEAPEGTESEMETPSAINGNPSWHLA
  DSPAVNGATGHSSSLDAREVIPMAAVKQALREAGDEFELRYRRAFSDLTSQLHITPGTAY
  QSFEQVVNELFRDGVNWGRIVAFFSFGGALCVESVDKEMQVLVSRIAAWMATYLNDHLEP
  WIQENGGWDTFVELYGNNAAAESRKGQERFNRWFLTGMTVAGVVLLGSLFSRK
• Function: Inhibits activation of caspases. Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis. Potent inhibitor of cell death.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  NF-kappa B signaling pathway (hsa04064)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Jak-STAT signaling pathway (hsa04630)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Toxoplasmosis (hsa05145)
  HTLV-I infection (hsa05166)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Pancreatic cancer (hsa05212)
  Chronic myeloid leukemia (hsa05220)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  The NLRP1 inflammasome (R-HSA-844455)
  BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members (R-HSA-111453)

Molecular Interaction Atlas (MIA) of This DTT

4 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	[2], [3], [4]
Obatoclax	DMPF9ZM	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]
APG-1252	DM8O3R9	Small-cell lung cancer	2C25.Y	Phase 1/2	[5]
AZD0466	DMWLZI6	Hematologic tumour	2B33.Y	Phase 1/2	[6]

7 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	[7]
Indole-based analog 3	DMTEYQJ	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-10	DMFKS2P	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-18	DM73S2C	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-21	DM18UA5	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-26	DM8GOH3	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-27	DMV6MLC	N. A.	N. A.	Patented	[7]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4'-FLUORO-1,1'-BIPHENYL-4-CARBOXYLIC ACID	DMQ1D9A	Discovery agent	N.A.	Investigative	[8]
E-003	DMA9CZV	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]
EAPB0203	DMB7685	T-cell leukaemia	2A90	Investigative	[10]
WEHI-0103122	DMK0OVE	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	7.28E-13	-0.55	-0.68

References

• [1] 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.
• [2] Clinical pipeline report, company report or official report of Roche (2009).
• [3] ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2008 Oct;7(10):3265-74.
• [4] ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8.
• [5] Bcl-2/Bcl-xl inhibitor APG-1252-M1 is a promising therapeutic strategy for gastric carcinoma. Cancer Med. 2020 Jun;9(12):4197-4206.
• [6] 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.
• [7] Mcl-1 inhibitors: a patent review.Expert Opin Ther Pat. 2017 Feb;27(2):163-178.
• [8] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [9] 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. (Target id: 2845).
• [10] EAPB0203, a member of the imidazoquinoxaline family, inhibits growth and induces caspase-dependent apoptosis in T-cell lymphomas and HTLV-I-associated adult T-cell leukemia/lymphoma. Blood. 2008 Apr 1;111(7):3770-7.