Target Information

Target General Information

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Target ID

T75596 (Former ID: TTDR00721)

Target Name

Methionine aminopeptidase 2 (METAP2)

Synonyms

Peptidase M 2; P67eIF2; P67; MetAP 2; METAP2; Initiation factor 2 associated 67 kDa glycoprotein; (MetAP)-2

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Gene Name

METAP2

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

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

Function

Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val).

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BioChemical Class

Peptidase

UniProt ID

MAP2_HUMAN

EC Number

EC 3.4.11.18

Sequence

MAGVEEVAASGSHLNGDLDPDDREEGAASTAEEAAKKKRRKKKKSKGPSAAGEQEPDKES
GASVDEVARQLERSALEDKERDEDDEDGDGDGDGATGKKKKKKKKKRGPKVQTDPPSVPI
CDLYPNGVFPKGQECEYPPTQDGRTAAWRTTSEEKKALDQASEEIWNDFREAAEAHRQVR
KYVMSWIKPGMTMIEICEKLEDCSRKLIKENGLNAGLAFPTGCSLNNCAAHYTPNAGDTT
VLQYDDICKIDFGTHISGRIIDCAFTVTFNPKYDTLLKAVKDATNTGIKCAGIDVRLCDV
GEAIQEVMESYEVEIDGKTYQVKPIRNLNGHSIGQYRIHAGKTVPIVKGGEATRMEEGEV
YAIETFGSTGKGVVHDDMECSHYMKNFDVGHVPIRLPRTKHLLNVINENFGTLAFCRRWL
DRLGESKYLMALKNLCDLGIVDPYPPLCDIKGSYTAQFEHTILLRPTCKEVVSRGDDY

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

Beloranib

Drug Info

Phase 3

Solid tumour/cancer

[2], [3]

ZGN-1061

Drug Info

Phase 2

Type 2 diabetes

[4]

M8891

Drug Info

Phase 1

Solid tumour/cancer

[5]

PPI-2458

Drug Info

Phase 1

Autoimmune diabetes

[6]

SDX-7320

Drug Info

Phase 1

Solid tumour/cancer

[5]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

TNP-470

Drug Info

Discontinued in Phase 2

Solid tumour/cancer

[7]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 30 Inhibitor drugs

Beloranib

Drug Info

[1], [8]

D-Methionine

Drug Info

[9]

ZGN-1061

Drug Info

[10]

M8891

Drug Info

[5]

PPI-2458

Drug Info

[11]

SDX-7320

Drug Info

[5]

TNP-470

Drug Info

[12]

2-(4-fluorophenylsulfonamido)-1-naphthoic acid

Drug Info

[13]

2-(phenylsulfonamido)-1-naphthoic acid

Drug Info

[13]

2-(phenylsulfonamido)-5-propylbenzoic acid

Drug Info

[13]

2-(pyridin-2-yl)-1H-benzo[d]imidazol-5-amine

Drug Info

[14]

2-(pyridin-2-yl)-1H-benzo[d]imidazole

Drug Info

[14]

2-(pyridin-2-yl)-1H-imidazo[4,5-c]pyridine

Drug Info

[14]

2-(thiazol-4-yl)-1H-benzo[d]imidazol-5-amine

Drug Info

[14]

2-Methyl-2-Propanol

Drug Info

[9]

3,5,6,8-Tetramethyl-N-Methyl Phenanthrolinium

Drug Info

[9]

3,5-dimethyl-2-(phenylsulfonamido)benzoic acid

Drug Info

[13]

3-anilino-5-benzylthio-1,2,4-triazole

Drug Info

[15]

5-bromo-2-(4-chlorophenylsulfonamido)benzoic acid

Drug Info

[13]

5-butyl-2-(phenylsulfonamido)benzoic acid

Drug Info

[13]

5-chloro-2-(pyridin-2-yl)-1H-benzo[d]imidazole

Drug Info

[14]

5-ethyl-2-(phenylsulfonamido)benzoic acid

Drug Info

[13]

5-fluoro-2-(pyridin-2-yl)-1H-benzo[d]imidazole

Drug Info

[14]

5-methyl-2-(phenylsulfonamido)benzoic acid

Drug Info

[16], [17]

5-methyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole

Drug Info

[14]

5-p-Tolyl-1H-[1,2,3]triazole

Drug Info

[18]

A-357300

Drug Info

[12]

Ovalicin

Drug Info

[9]

OXYQUINOLINE

Drug Info

[14]

XMT-1191

Drug Info

[20]

Binder

[+] 1 Binder drugs

Fumagillin

Drug Info

[19]

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: D-methionine

Ligand Info

Structure Description

Human methionine aminopeptidase type II in complex with D-methionine

PDB:1KQ0

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[21]

PDB Sequence

VQTDPPSVPI

¹²⁰

CDLYPNGVFP

¹³⁰

KGQECEYPEE

¹⁵⁴

KKALDQASEE

¹⁶⁴

IWNDFREAAE

¹⁷⁴

AHRQVRKYVM

¹⁸⁴

SWIKPGMTMI

¹⁹⁴

EICEKLEDCS

²⁰⁴

RKLIKENGLN

²¹⁴

AGLAFPTGCS

²²⁴

LNNCAAHYTP

²³⁴

NAGDTTVLQY

²⁴⁴

DDICKIDFGT

²⁵⁴

HISGRIIDCA

²⁶⁴

FTVTFNPKYD

²⁷⁴

TLLKAVKDAT

²⁸⁴

NTGIKCAGID

²⁹⁴

VRLCDVGEAI

³⁰⁴

QEVMESYEVE

³¹⁴

IDGKTYQVKP

³²⁴

IRNLNGHSIG

³³⁴

QYRIHAGKTV

³⁴⁴

PIIKGGEATR

³⁵⁴

MEEGEVYAIE

³⁶⁴

TFGSTGKGVV

³⁷⁴

HDDMECSHYM

³⁸⁴

KNFDVGHVPI

³⁹⁴

RLPRTKHLLN

⁴⁰⁴

VINENFGTLA

⁴¹⁴

FCRRWLDRLG

⁴²⁴

ESKYLMALKN

⁴³⁴

LCDLGIVDPY

⁴⁴⁴

PPLCDIKGSY

⁴⁵⁴

TAQFEHTILL

⁴⁶⁴

RPTCKEVVSR

⁴⁷⁴

GDDY

Residue

Distance (Å)

PHE219

3.814

PRO220

4.380

HIS231

3.037

ASP251

3.016

ASP262

3.534

HIS331

3.147

ILE338

4.035

Residue

Distance (Å)

HIS339

2.172

GLU364

4.223

HIS382

3.611

MET384

4.993

ALA414

4.054

TYR444

4.510

GLU459

4.507

Ligand Name: Fumagillin

Ligand Info

Structure Description

HUMAN METHIONINE AMINOPEPTIDASE 2 COMPLEXED WITH ANGIOGENESIS INHIBITOR FUMAGILLIN

PDB:1BOA

Method

X-ray diffraction

Resolution

1.80 Å

Mutation

[22]

PDB Sequence

KVQTDPPSVP

¹¹⁹

ICDLYPNGVF

¹²⁹

PKGQECEYPE

¹⁵⁴

KKALDQASEE

¹⁶⁴

IWNDFREAAE

¹⁷⁴

AHRQVRKYVM

¹⁸⁴

SWIKPGMTMI

¹⁹⁴

EICEKLEDCS

²⁰⁴

RKLIKENGLN

²¹⁴

AGLAFPTGCS

²²⁴

LNNCAAHYTP

²³⁴

NAGDTTVLQY

²⁴⁴

DDICKIDFGT

²⁵⁴

HISGRIIDCA

²⁶⁴

FTVTFNPKYD

²⁷⁴

TLLKAVKDAT

²⁸⁴

NTGIKCAGID

²⁹⁴

VRLCDVGEAI

³⁰⁴

QEVMESYEVE

³¹⁴

IDGKTYQVKP

³²⁴

IRNLNGHSIG

³³⁴

QYRIHAGKTV

³⁴⁴

PIIKGGEATR

³⁵⁴

MEEGEVYAIE

³⁶⁴

TFGSTGKGVV

³⁷⁴

HDDMECSHYM

³⁸⁴

KNFDVGHVPI

³⁹⁴

RLPRTKHLLN

⁴⁰⁴

VINENFGTLA

⁴¹⁴

FCRRWLDRLG

⁴²⁴

ESKYLMALKN

⁴³⁴

LCDLGIVDPY

⁴⁴⁴

PPLCDIKGSY

⁴⁵⁴

TAQFEHTILL

⁴⁶⁴

RPTCKEVVSR

⁴⁷⁴

GDDY

Residue

Distance (Å)

PHE219

3.802

PRO220

4.746

ALA230

4.150

HIS231

1.484

ASP262

4.326

ASN327

3.273

LEU328

3.596

ASN329

3.245

GLY330

4.031

HIS331

3.566

ILE338

3.704

HIS339

3.620

Residue

Distance (Å)

THR343

4.757

GLU364

3.602

PHE366

4.095

VAL374

3.744

HIS375

3.662

ASP376

2.940

HIS382

4.007

MET384

3.863

ALA414

3.905

TYR444

3.540

LEU447

3.938

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). 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 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).

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

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.

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.07E-04	Radiality	3.98E-03	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.00E+00	Topological coefficient	.	Eccentricity	1
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

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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Reactome

[+] 1 Reactome Pathways

Inactivation, recovery and regulation of the phototransduction cascade

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

2011 Pipeline of Zafgen.

REF 2

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: 8445).

REF 3

ClinicalTrials.gov (NCT02179151) Double-Blind, Placebo Controlled, Phase 3 Trial of ZGN-440 (Beloranib) in Obese Subjects With Prader-Willi Syndrome. U.S. National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT03254368) Study to Assess the Effects and Safety of ZGN-1061 in Overweight and Obese Participants With Type 2 Diabetes. U.S. National Institutes of Health.

REF 5

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

REF 6

ClinicalTrials.gov (NCT00100347) Safety/Tolerance Study of PPI-2458 in Subjects With Non-Hodgkin's Lymphoma and Solid Tumors. U.S. National Institutes of Health.

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001587)

REF 8

Inhibition of the methionine aminopeptidase 2 enzyme for the treatment of obesity. Diabetes Metab Syndr Obes. 2014 Feb 28;7:73-84.

REF 9

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 10

The methionine aminopeptidase 2 inhibitor ZGN-1061 improves glucose control and weight in overweight and obese individuals with type 2 diabetes: A randomized, placebo-controlled trial. Diabetes Obes Metab. 2020 Jul;22(7):1215-1219.

REF 11

Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and in vivo activity. Drug Metab Dispos. 2013 Apr;41(4):814-26.

REF 12

Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2. Cancer Res. 2003 Nov 15;63(22):7861-9.

REF 13

Development of sulfonamide compounds as potent methionine aminopeptidase type II inhibitors with antiproliferative properties. Bioorg Med Chem Lett. 2006 Jul 1;16(13):3574-7.

REF 14

Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors, Bioorg. Med. Chem. Lett. 20(14):4038-4044 (2010).

REF 15

Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J Med Chem. 2007 Aug 9;50(16):3777-85.

REF 16

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 17

Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of a... J Med Chem. 2006 Jun 29;49(13):3832-49.

REF 18

4-Aryl-1,2,3-triazole: a novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo. J Med Chem. 2005 Sep 8;48(18):5644-7.

REF 19

Homology modeling and calculation of the cobalt cluster charges of the Encephazlitozoon cuniculi methionine aminopeptidase, a potential target for drug design. Biophys Chem. 2003 Aug 1;105(1):29-43.

REF 20

REF 21

Human methionine aminopeptidase type 2 in complex with L- and D-methionine. Bioorg Med Chem Lett. 2006 May 15;16(10):2580-3.

REF 22

Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science. 1998 Nov 13;282(5392):1324-7.

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