Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTL53M6)

• DTT Name: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)
• Synonyms: mcl1/EAT; Bcl2-L-3; Bcl-2-related protein EAT/mcl1; Bcl-2-like protein 3; BCL2L3
• Gene Name: MCL1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: B-cell lymphoma Bcl-2
• UniProt ID: MCL1_HUMAN
• TTD ID: T14912
• Sequence:
  MFGLKRNAVIGLNLYCGGAGLGAGSGGATRPGGRLLATEKEASARREIGGGEAGAVIGGS
  AGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIM
  SPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLE
  IISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNE
  DDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVR
  TKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR
• Function: Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation.
• KEGG Pathway:
  PI3K-Akt signaling pathway (hsa04151)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway: Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DTT

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Obatoclax	DMPF9ZM	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]
ABBV-467	DM87SM9	Multiple myeloma	2A83	Phase 1	[2]
AMG 176	DM0Q7NO	Acute myeloid leukaemia	2A60	Phase 1	[3]
AMG 397	DM7CNTG	Refractory hematologic malignancy	2A85.5	Phase 1	[4]
AZD5991	DM7QGHO	Haematological malignancy	2B33.Y	Phase 1	[3]
MIK665	DMTUVCG	Acute myeloid leukaemia	2A60	Phase 1	[5]
PRT1419	DMIKE0O	Melanoma	2C30	Phase 1	[6]

22 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Biphenyl carboxylic acid derivative 1	DMPWFJN	N. A.	N. A.	Patented	[7]
Biphenyl carboxylic acid derivative 2	DM6TXF4	N. A.	N. A.	Patented	[7]
Indole-based analog 1	DMIGS81	N. A.	N. A.	Patented	[7]
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-13	DMCFOXP	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-18	DM73S2C	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-19	DM214WA	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-20	DMD0T6S	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-21	DM18UA5	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-22	DMM6FOW	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-23	DMXA70C	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]
PMID27744724-Compound-28	DMB018S	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-29	DM2GDXH	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-3	DMWKYU4	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-4	DMV1WND	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-5	DM6UTAQ	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-6	DMV7P4N	N. A.	N. A.	Patented	[7]
PMID27744724-Compound-Fomula2	DMT2W97	N. A.	N. A.	Patented	[7]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BITHIONOL	DMPJKRL	Trematode infection	1F8Y	Withdrawn from market	[8]
Sch-45752	DME9Q3V	Asthma	CA23	Terminated	[8]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALTENUSIN	DMYCS0B	Discovery agent	N.A.	Investigative	[8]
AMENTOFLAVONE	DMLRNV2	Discovery agent	N.A.	Investigative	[8]
EU-517	DMZ1FCJ	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]
GNF-PF-1591	DMHCGBZ	Discovery agent	N.A.	Investigative	[8]
GNF-PF-3955	DMOJL61	Discovery agent	N.A.	Investigative	[8]
GNF-PF-5134	DM7850H	Discovery agent	N.A.	Investigative	[8]
MORIN	DM2OGZ5	Discovery agent	N.A.	Investigative	[8]
NSC-180246	DMXBRCI	Discovery agent	N.A.	Investigative	[8]
NSC-66209	DMQ0S4B	Discovery agent	N.A.	Investigative	[8]
QEDIIRNIARHLAQVGDSMDR	DMJ38YV	Discovery agent	N.A.	Investigative	[10]
ROSMARINIC ACID	DMQ6SJT	Rheumatoid arthritis	FA20	Investigative	[8]
SULFURETIN	DMYPM2D	Discovery agent	N.A.	Investigative	[8]
TW-37	DMDE8YS	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.06E-04	1.29	2.97

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 AbbVie.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of Amgen.
• [5] MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells. Cell Death Dis. 2020 Jun 8;11(6):443.
• [6] Clinical pipeline report, company report or official report of Prelude Therapeutics.
• [7] Mcl-1 inhibitors: a patent review.Expert Opin Ther Pat. 2017 Feb;27(2):163-178.
• [8] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [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: 2847).
• [10] Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem. 2006 Oct 19;49(21):6139-42.