Target Information

Target General Information

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Target ID

T14912 (Former ID: TTDC00048)

Target 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

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Gene Name

MCL1

Target Type

Clinical trial target

[1]

Disease

[+] 6 Target-related Diseases

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

Acute myeloid leukaemia [ICD-11: 2A60]

Malignant haematopoietic neoplasm [ICD-11: 2B33]

Mature B-cell lymphoma [ICD-11: 2A85]

Melanoma [ICD-11: 2C30]

Multiple myeloma [ICD-11: 2A83]

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.

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BioChemical Class

B-cell lymphoma Bcl-2

UniProt ID

MCL1_HUMAN

Sequence

MFGLKRNAVIGLNLYCGGAGLGAGSGGATRPGGRLLATEKEASARREIGGGEAGAVIGGS
AGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIM
SPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLE
IISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNE
DDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVR
TKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T75HMM

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

Obatoclax

Drug Info

Phase 2

Solid tumour/cancer

[1]

AMG 176

Drug Info

Phase 1

Multiple myeloma

[6]

AZD5991

Drug Info

Phase 1

Haematological malignancy

[6]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

BITHIONOL

Drug Info

Withdrawn from market

Trematode infection

[7], [8]

Sch-45752

Drug Info

Terminated

Asthma

[9]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 37 Inhibitor drugs

Obatoclax

Drug Info

[1]

AMG 176

Drug Info

[6]

AZD5991

Drug Info

[6]

Biphenyl carboxylic acid derivative 1

Drug Info

[10]

Biphenyl carboxylic acid derivative 2

Drug Info

[10]

Indole-based analog 1

Drug Info

[10]

Indole-based analog 2

Drug Info

[10]

Indole-based analog 3

Drug Info

[10]

PMID27744724-Compound-10

Drug Info

[10]

PMID27744724-Compound-13

Drug Info

[10]

PMID27744724-Compound-18

Drug Info

[10]

PMID27744724-Compound-19

Drug Info

[10]

PMID27744724-Compound-20

Drug Info

[10]

PMID27744724-Compound-21

Drug Info

[10]

PMID27744724-Compound-22

Drug Info

[10]

PMID27744724-Compound-23

Drug Info

[10]

PMID27744724-Compound-26

Drug Info

[10]

PMID27744724-Compound-27

Drug Info

[10]

PMID27744724-Compound-28

Drug Info

[10]

PMID27744724-Compound-29

Drug Info

[10]

PMID27744724-Compound-3

Drug Info

[10]

PMID27744724-Compound-4

Drug Info

[10]

PMID27744724-Compound-5

Drug Info

[10]

PMID27744724-Compound-6

Drug Info

[10]

PMID27744724-Compound-Fomula2

Drug Info

[10]

BITHIONOL

Drug Info

[11]

Sch-45752

Drug Info

[11]

ALTENUSIN

Drug Info

[11]

AMENTOFLAVONE

Drug Info

[11]

GNF-PF-1591

Drug Info

[11]

GNF-PF-3955

Drug Info

[11]

GNF-PF-5134

Drug Info

[11]

MORIN

Drug Info

[11]

QEDIIRNIARHLAQVGDSMDR

Drug Info

[12]

ROSMARINIC ACID

Drug Info

[11]

SULFURETIN

Drug Info

[11]

TW-37

Drug Info

[12]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Norleucine

Ligand Info

Structure Description

Human Mcl-1 in complex with a modified unnatural Bim BH3 peptide

PDB:6UAB

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[13]

PDB Sequence

SDELYRQSLE

¹⁸⁰

IISRYLREQA

¹⁹⁰

TGAKDTKPMG

²⁰⁰

RSGATSRKAL

²¹⁰

ETLRRVGDGV

²²⁰

QRNHETAFQG

²³⁰

MLRKLDIKNE

²⁴⁰

DDVKSLSRVM

²⁵⁰

IHVFSDGVTN

²⁶⁰

WGRIVTLISF

²⁷⁰

GAFVAKHLKT

²⁸⁰

INQESCIEPL

²⁹⁰

AESITDVLVR

³⁰⁰

TKRDWLVKQR

³¹⁰

GWDGFVEFFH

³²⁰

VEDLE

Residue

Distance (Å)

MET231

4.037

LYS234

3.434

Residue

Distance (Å)

LEU235

3.290

VAL249

4.349

Ligand Name: AZD5991

Ligand Info

Structure Description

INDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX IN COMPLEX WITH AZD5991

PDB:6FS0

Method

X-ray diffraction

Resolution

2.25 Å

Mutation

[14]

PDB Sequence

GPLGSEDDLY

¹⁷⁵

RQSLEIISRY

¹⁸⁵

LREQATGSKD

¹⁹⁵

SKPLGEAGAA

²⁰⁵

GRRALETLRR

²¹⁵

VGDGVQRNHE

²²⁵

TAFQGMLRKL

²³⁵

DIKNEDDVKS

²⁴⁵

LSRVMIHVFS

²⁵⁵

DGVTNWGRIV

²⁶⁵

TLISFGAFVA

²⁷⁵

KHLKTINQES

²⁸⁵

CIEPLAESIT

²⁹⁵

DVLVRTKRDW

³⁰⁵

LVKQRGWDGF

³¹⁵

VEFFHV

Residue

Distance (Å)

HIS224

4.032

ALA227

3.462

PHE228

3.559

MET231

3.453

LEU235

3.792

LEU246

4.171

VAL249

3.549

MET250

3.871

VAL253

3.283

Residue

Distance (Å)

PHE254

3.868

ARG263

2.807

THR266

3.598

LEU267

3.246

PHE270

3.485

GLY271

3.681

VAL274

4.504

LEU290

3.984

ILE294

3.791

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
JAK-STAT signaling pathway	hsa04630	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy

Degree	25	Degree centrality	2.69E-03	Betweenness centrality	1.20E-03
Closeness centrality	2.56E-01	Radiality	1.44E+01	Clustering coefficient	1.70E-01
Neighborhood connectivity	4.34E+01	Topological coefficient	6.01E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

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

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KEGG Pathway

[+] 2 KEGG Pathways

PI3K-Akt signaling pathway

MicroRNAs in cancer

NetPath Pathway

[+] 1 NetPath Pathways

TCR Signaling Pathway

Panther Pathway

[+] 2 Panther Pathways

Apoptosis signaling pathway

CCKR signaling map ST

PID Pathway

[+] 4 PID Pathways

E2F transcription factor network

Direct p53 effectors

IL6-mediated signaling events

HIF-1-alpha transcription factor network

WikiPathways

[+] 5 WikiPathways

Apoptosis

miR-targeted genes in muscle cell - TarBase

miR-targeted genes in lymphocytes - TarBase

miR-targeted genes in leukocytes - TarBase

Apoptosis Modulation and Signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 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.

REF 2

ClinicalTrials.gov (NCT04178902) A Study of the Safety and Tolerability of ABBV-467 in Adult Participants With Relapsed/Refractory (R/R) Multiple Myeloma. U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT04543305) A Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies. U.S. National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT02979366) Phase I Study of S64315 Administred Intravenously in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome. U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT03465540) Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies. U.S. National Institutes of Health.

REF 6

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

REF 7

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: 2338).

REF 8

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

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002639)

REF 10

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

REF 11

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.

REF 12

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 13

Inhibitor peptides against Mcl-1 containing non-natural amino acids show potent apoptotic response.

REF 14

Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018 Dec 17;9(1):5341.

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