Targeting the polyamine pathway with transition-state analogue inhibitors of 5'-methylthioadenosine phosphorylase.
Article Details
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Evans GB, Furneaux RH, Schramm VL, Singh V, Tyler PC
Targeting the polyamine pathway with transition-state analogue inhibitors of 5'-methylthioadenosine phosphorylase.
J Med Chem. 2004 Jun 3;47(12):3275-81.
- PubMed ID
- 15163207 [ View in PubMed]
- Abstract
The polyamine biosynthetic pathway is a therapeutic target for proliferative diseases because cellular proliferation requires elevated levels of polyamines. A byproduct of the latter stages of polyamine biosynthesis (the synthesis of spermidine and spermine) is 5'-methylthioadenosine (MTA). In humans, MTA is processed by 5'-methylthioadenosine phosphorylase (MTAP) so that significant amounts of MTA do not accumulate. Potent inhibitors of MTAP might allow the buildup of sufficient levels of MTA to generate feedback inhibition of polyamine biosynthesis. We have designed and synthesized a family of potential transition-state analogue inhibitors of MTAP on the basis of our knowledge of the transition-state structure of purine nucleoside phosphorylase and the assumption that it is likely the two enzymes share a common catalytic mechanism. Several of the inhibitors display slow-onset tight-binding properties, consistent with them being transition-state analogues, with the most potent having a dissociation constant of 166 pM.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Forodesine Purine nucleoside phosphorylase Ki (nM) 0.056 N/A N/A Details