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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
Structure for PPI-2458 (DB05864)
- Weight
- Average: 424.531
Monoisotopic: 424.257336894 - Chemical Formula
- C22H36N2O6
- Synonyms
- Not Available
Pharmacology
- Indication
Investigated for use/treatment in lymphoma (non-hodgkin's) and solid tumors.
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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.
Target Actions Organism AMethionine aminopeptidase 2 inhibitorHumans - 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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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
- 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]
- 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]
- 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]
- External Links
- PubChem Compound
- 6918653
- PubChem Substance
- 175427046
- ChemSpider
- 5293846
- BindingDB
- 50088527
- ChEMBL
- CHEMBL3527358
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data1 Terminated Treatment Non-Hodgkin's Lymphoma (NHL) / Solid Tumors 1 somestatus stop reason just information to hide
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
Property Value Source Water Solubility 0.0439 mg/mL ALOGPS logP 2.07 ALOGPS logP 2.07 Chemaxon logS -4 ALOGPS pKa (Strongest Acidic) 13.45 Chemaxon pKa (Strongest Basic) -3.6 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 115.71 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 110.43 m3·mol-1 Chemaxon Polarizability 46.27 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.7556 Blood Brain Barrier - 0.8091 Caco-2 permeable - 0.6341 P-glycoprotein substrate Substrate 0.7839 P-glycoprotein inhibitor I Inhibitor 0.6649 P-glycoprotein inhibitor II Non-inhibitor 0.6262 Renal organic cation transporter Non-inhibitor 0.9387 CYP450 2C9 substrate Non-substrate 0.8949 CYP450 2D6 substrate Non-substrate 0.8349 CYP450 3A4 substrate Substrate 0.6579 CYP450 1A2 substrate Non-inhibitor 0.7392 CYP450 2C9 inhibitor Non-inhibitor 0.752 CYP450 2D6 inhibitor Non-inhibitor 0.887 CYP450 2C19 inhibitor Non-inhibitor 0.724 CYP450 3A4 inhibitor Non-inhibitor 0.8011 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8873 Ames test Non AMES toxic 0.5451 Carcinogenicity Non-carcinogens 0.9117 Biodegradation Not ready biodegradable 0.9939 Rat acute toxicity 2.7785 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9931 hERG inhibition (predictor II) Non-inhibitor 0.8345
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a6r-0022900000-cf8d2a59c2e367f84df3 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-01bc-2912300000-5d492fda5371eedf44f9 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-3937700000-e2701a8e2988f20905c9 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-9230000000-2074131eb9767bc6356a Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-9454100000-5ad4b7e4edcaf6706d02 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-052f-9763100000-2bffeb64548dc7ec7f35 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 207.17189 predictedDeepCCS 1.0 (2019) [M+H]+ 209.1989 predictedDeepCCS 1.0 (2019) [M+Na]+ 215.11143 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General 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). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo
- Specific Function
- aminopeptidase activity
- Gene Name
- METAP2
- Uniprot ID
- P50579
- Uniprot Name
- Methionine aminopeptidase 2
- Molecular Weight
- 52891.145 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Drug created at November 18, 2007 18:28 / Updated at August 26, 2024 19:22