NAV

PPI-2458

Identification

Generic Name
PPI-2458
DrugBank Accession Number
DB05864
Background

PPI-2458 represents a potentially new and important addition to the growing list of therapeutics aimed at specific molecular oncology targets. PPI-2458 is a novel, proprietary molecule belonging to the fumagillin class of compounds that specifically targets the MetAP-2 enzyme. This class of compounds has been shown to prevent both abnormal cell growth and the formation of new blood vessels (known as angiogenesis), which contribute to the growth of aberrant tissues in diseases such as cancer and rheumatoid arthritis. Clinical development with previous fumagillin derivatives has been limited by their toxicity profile. In preclinical studies to date, PPI-2458 has demonstrated the potent pharmacologic activity of this class of compounds while displaying an improved pharmacokinetic and toxicity profile.

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 424.531
Monoisotopic: 424.257336894
Chemical Formula
C22H36N2O6
Synonyms
Not Available
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Pharmacology

Indication

Investigated for use/treatment in lymphoma (non-hodgkin's) and solid tumors.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

PPI-2458's potent inhibition of MetAP-2 presents the potential for use as a new therapy for non-Hodgkin's lymphoma (NHL). MetAP-2 is highly expressed in human germinal center B cells. The neoplastic counterparts of these cells are the cell types observed in certain NHL subtypes, such as diffuse large B cell lymphoma and follicular lymphoma. PPI-2458 has been shown to reduce the formation of germinal centers in lymphoid tissues in vivo, have direct anti-proliferative activity on NHL cells in vitro and inhibit the growth of NHL tumors in a preclinical model in vivo. The anti-tumor activity of PPI-2458 was dose-dependent in this preclinical in vivo model and directly correlated with the level of molecular target MetAP-2 enzyme inhibition in tumor tissue, as measured by a proprietary, pharmacodynamic assay developed by PRAECIS. Additionally, the activity of PPI-2458 in this preclinical model was synergistic with several chemotherapeutic agents that are routinely used in combination in NHL patients.

TargetActionsOrganism
UMethionine aminopeptidase 2Not AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as valine and derivatives. These are compounds containing valine or a derivative thereof resulting from reaction of valine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Valine and derivatives
Alternative Parents
Fatty amides / Carbamate esters / Primary carboxylic acid amides / Organic carbonic acids and derivatives / Oxacyclic compounds / Epoxides / Dialkyl ethers / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Aliphatic heteropolycyclic compound / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxamide group / Dialkyl ether / Ether / Fatty acyl / Fatty amide / Hydrocarbon derivative
show 11 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
NA0Y2SRR29
CAS number
Not Available
InChI Key
QBDVVYNLLXGUGN-XGTBZJOHSA-N
InChI
InChI=1S/C22H36N2O6/c1-12(2)7-8-15-21(5,30-15)18-17(27-6)14(9-10-22(18)11-28-22)29-20(26)24-16(13(3)4)19(23)25/h7,13-18H,8-11H2,1-6H3,(H2,23,25)(H,24,26)/t14-,15-,16-,17-,18-,21+,22+/m1/s1
IUPAC Name
(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl N-[(1R)-1-carbamoyl-2-methylpropyl]carbamate
SMILES
[H][C@@]1([C@H](OC)[C@@H](CC[C@]11CO1)OC(=O)N[C@H](C(C)C)C(N)=O)[C@@]1(C)O[C@@H]1CC=C(C)C

References

General References
  1. Lazarus DD, Doyle EG, Bernier SG, Rogers AB, Labenski MT, Wakefield JD, Karp RM, Clark EJ, Lorusso J, Hoyt JG, Thompson CD, Hannig G, Westlin WF: An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis. Inflamm Res. 2008 Jan;57(1):18-27. doi: 10.1007/s00011-007-7075-5. [Article]
  2. Cooper AC, Karp RM, Clark EJ, Taghizadeh NR, Hoyt JG, Labenski MT, Murray MJ, Hannig G, Westlin WF, Thompson CD: A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo. Clin Cancer Res. 2006 Apr 15;12(8):2583-90. [Article]
  3. Hannig G, Lazarus DD, Bernier SG, Karp RM, Lorusso J, Qiu D, Labenski MT, Wakefield JD, Thompson CD, Westlin WF: Inhibition of melanoma tumor growth by a pharmacological inhibitor of MetAP-2, PPI-2458. Int J Oncol. 2006 Apr;28(4):955-63. [Article]
PubChem Compound
6918653
PubChem Substance
175427046
ChemSpider
5293846
BindingDB
50088527
ChEMBL
CHEMBL3527358

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedTreatmentNon-Hodgkin's Lymphoma (NHL) / Solid Tumors1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0439 mg/mLALOGPS
logP2.07ALOGPS
logP2.07Chemaxon
logS-4ALOGPS
pKa (Strongest Acidic)13.45Chemaxon
pKa (Strongest Basic)-3.6Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area115.71 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity110.43 m3·mol-1Chemaxon
Polarizability46.27 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.7556
Blood Brain Barrier-0.8091
Caco-2 permeable-0.6341
P-glycoprotein substrateSubstrate0.7839
P-glycoprotein inhibitor IInhibitor0.6649
P-glycoprotein inhibitor IINon-inhibitor0.6262
Renal organic cation transporterNon-inhibitor0.9387
CYP450 2C9 substrateNon-substrate0.8949
CYP450 2D6 substrateNon-substrate0.8349
CYP450 3A4 substrateSubstrate0.6579
CYP450 1A2 substrateNon-inhibitor0.7392
CYP450 2C9 inhibitorNon-inhibitor0.752
CYP450 2D6 inhibitorNon-inhibitor0.887
CYP450 2C19 inhibitorNon-inhibitor0.724
CYP450 3A4 inhibitorNon-inhibitor0.8011
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8873
Ames testNon AMES toxic0.5451
CarcinogenicityNon-carcinogens0.9117
BiodegradationNot ready biodegradable0.9939
Rat acute toxicity2.7785 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9931
hERG inhibition (predictor II)Non-inhibitor0.8345
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a6r-0022900000-cf8d2a59c2e367f84df3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-01bc-2912300000-5d492fda5371eedf44f9
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-3937700000-e2701a8e2988f20905c9
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9230000000-2074131eb9767bc6356a
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-9454100000-5ad4b7e4edcaf6706d02
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-052f-9763100000-2bffeb64548dc7ec7f35
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-207.17189
predicted
DeepCCS 1.0 (2019)
[M+H]+209.1989
predicted
DeepCCS 1.0 (2019)
[M+Na]+215.11143
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Methionine aminopeptidase 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Poly(a) rna binding
Specific 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...
Gene Name
METAP2
Uniprot ID
P50579
Uniprot Name
Methionine aminopeptidase 2
Molecular Weight
52891.145 Da

Drug created at November 18, 2007 18:28 / Updated at June 12, 2020 16:52