Targeting the polyamine pathway with transition-state analogue inhibitors of 5'-methylthioadenosine phosphorylase.
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.
Evans
Gary B
GB
Carbohydrate Chemistry, Industrial Research Limited, P.O. Box 31310, Lower Hutt, New Zealand.
Furneaux
Richard H
RH
Schramm
Vern L
VL
Singh
Vipender
V
Tyler
Peter C
PC
D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011073:Polyamines / Q000378:metabolism*; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C487416:5'-methylthio-immucillin A; D011073:Polyamines; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; D011759:Pyrrolidines; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000225:Adenine