Probing the peptidylglycine alpha-hydroxylating monooxygenase active site with novel 4-phenyl-3-butenoic acid based inhibitors.
Specific inhibition of the copper-containing peptidylglycine alpha-hydroxylating monooxygenase (PHM), which catalyzes the post-translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure-activity study of new compounds derived from a well-known PHM substrate analogue, the olefinic compound 4-phenyl-3-butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d, for example, bears a meta-benzyloxy substituent, and exhibits better inhibition features (K(i)=3.9 microM, k(inact)/K(i)=427 M(-1) s(-1)) than the parent PBA (K(i)=19 microM, k(inact)/K(i)=82 M(-1) s(-1)). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features.
Langella
Emma
E
Istituto di Biostrutture e Bioimmagini, CNR via Mezzocannone 16, 80134 Napoli, Italy.
Pierre
Sébastien
S
Ghattas
Wadih
W
Giorgi
Michel
M
Réglier
Marius
M
Saviano
Michele
M
Esposito
Luciana
L
Hardré
Renaud
R
D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010654:Phenylbutyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
C554618:4-(3-benzyloxy-4-methoxy)phenyl-3-butenoic acid; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D009097:Multienzyme Complexes; D010654:Phenylbutyrates; C064180:4-phenyl-3-butenoic acid; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase