Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha).
Dipeptidyl peptidase IV (DPP-IV) and seprase belong to a small group of membrane-bound, proline-specific serine proteases, the serine integral membrane proteases (SIMPs). Whilst DPP-IV is the most exhaustively studied peptidase in this class, relatively less is known about the inhibitor/substrate specificity of its close homolog seprase. Additionally, whereas, DPP-IV expression is largely ubiquitous, seprase expression is restricted to tumour and tissue remodelling sites in vivo. Consequently, the highly restricted expression and distribution of seprase potentially make it an excellent therapeutic target for the modulation of neoplastic invasion and metastasis. Against this background, we now wish to report on the design, synthesis, and kinetic testing of a series of dipeptide proline diphenyl phosphonates, against DPP-IV and seprase. The most potent inhibitor of DPP-IV and seprase was found to be Gly-ProP(OPh)2, which exhibited overall second-order rate constants of inactivation of 5.24 x 105 M-1 min-1 and 1.06 x 104 M-1 min-1 against DPP-IV and seprase, respectively. Both proteases displayed differing profiles of susceptibility towards the other members of the series of inhibitors synthesised. In addition, Gly-ProP(OPh)2 and Tyr-ProP(OPh)2 were found to exert a considerable, dose-dependent anti-invasive effect on the LOX melanoma cell line, in vitro.
Gilmore
Brendan F
BF
School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
Lynas
John F
JF
Scott
Christopher J
CJ
McGoohan
Caroline
C
Martin
Lorraine
L
Walker
Brian
B
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D010450:Endopeptidases; D018093:Gelatinases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099167:Fibroblast Activation Protein Alpha
D000970:Antineoplastic Agents; D004151:Dipeptides; D018819:Dipeptidyl Peptidase 4; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D063065:Organophosphonates; D011392:Proline; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D000099167:Fibroblast Activation Protein Alpha; C512864:glycyl-proline diphenyl phosphonate; C512863:tyrosyl-proline diphenyl phosphonate