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

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]

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

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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

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