Synthesis and structure–activity relationship of N-acyl-Gly-, N-acyl-Sar- and N-blocked-boroPro inhibitors of FAP, DPP4, and POP

Tran, Thuy; Quan, Clifford; Edosada, Conrad Yap; Mayeda, Mark; Wiesmann, Christian; Sutherlin, Dan; Wolf, Beni B.

doi:10.1016/j.bmcl.2006.11.072

Cited by 47 publications

(55 citation statements)

References 12 publications

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“…36 Tran et al actually reported that 4 is only 3-fold selective for PREP over FAP, 22 a finding with which our results essentially agree (Table 1). Furthermore, Tran et al reported that a P 2 d -alanine-containing inhibitor, N-acetyl- d -Ala-boroPro ( 3 ), exhibits modest potency ( K i of 350 nM) and specificity (7.7-fold) for FAP over PREP.…”

Section: Resultssupporting

confidence: 86%

Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

Poplawski

Lai

et al. 2013

J. Med. Chem.

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Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-d-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.

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Section: Resultssupporting

confidence: 86%

Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

Poplawski

Lai

et al. 2013

J. Med. Chem.

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“…The first pharmacophore was described by Yoshimoto et al [60], but later SAR studies disclosed new shape features in order to achieve higher selectivity over other prolyl peptidase family proteases, mainly fibroblast activating protein (FAP) and dipeptidyl peptidase IV (DPPIV) [57,61]. In addition, the influence of the electrostatic environment of POP active site in the binding processes was also studied by Szeltner et al [62].…”

Section: The Pharmacophore Of Peptidomimetic Inhibitorsmentioning

confidence: 96%

Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010

Lopez

Tarragó

Giralt

2011

Expert Opinion on Therapeutic Patents

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The major part of the repertory of POP inhibitors derived from systematical modification of the canonical compound benzyloxycarbonyl-prolyl-prolinal (ZPP). Nevertheless, only two of them have progressed into the clinical trials. One possible reason for this failure is the lack of studies concerning pharmacodynamics, pharmacokinetics and toxicity, together with the absence of suitable animal models. Moreover, POP is still not a well-defined therapeutic target. Further studies are required for the elucidation of the biological role of POP and to validate the therapeutic action of inhibitors in cognitive processes. In contrast, the involvement of POP in protein-protein interactions together with the recent evidences in angiogenesis opens alternative approaches to the traditional active site-directed inhibitors, as well as new therapeutic applications.

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“…N-Acyl-Sar-boroPro analogs retained selectivity against DPPIV and potent POP inhibitory activity but displayed decreased Seprase inhibitory activity. These results provide a foundation for future studies aimed at developing selective inhibitors for Seprase and POP [97].…”

Section: Direct Inhibition Of Seprase Protease Activitymentioning

confidence: 99%

“…The most potent inhibitor for both enzymes was found to be Gly- In the case of Seprase, it was found that the nature of the P 2 residue of the inhibitor had a less pronounced effect on the second order rate constants, in contrast to DPPIV. A recent study by Tran [97] explored the structure-activity relationship of various Nacyl-Gly-, N-acyl-Sar-and N-blocked-boroProline derivatives against three prolyl peptidases, Seprase, DPPIV and POP. Several N-acyl-Gly-and N-blocked-boro compounds showed low nanomolar inhibitory activity against Seprase and POP and selectively against DPPIV.…”

Section: Direct Inhibition Of Seprase Protease Activitymentioning

confidence: 99%

Seprase: An overview of an important matrix serine protease

O’Brien¹,

O’Connor²

2008

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

121

104

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Seprase or Fibroblast activation protein (FAP) is an integral membrane serine peptidase, which has been shown to have gelatinase activity. Seprase has a dual function in tumour progression. The proteolytic activity of Seprase has been shown to promote cell invasiveness towards the ECM and also to support tumour growth and proliferation. Seprase appears to act as a proteolytically active 170-kDa dimer, consisting of two 97-kDa subunits. It is a member of the group type II integral serine proteases, which include dipeptidyl peptidase IV (DPPIV/CD26) and related type II trans-membrane prolyl serine peptidases, which exert their mechanisms of action on the cell surface. DPPIV and Seprase exhibit multiple functions due to their abilities to form complexes with each other and to interact with other membrane-associated molecules. Localization of these protease complexes at cell surface protrusions, called invadopodia, may have a prominent role in processing soluble factors and in the degradation of extracellular matrix components that are essential to the cellular migration and matrix invasion that occur during tumour invasion, metastasis and angiogenesis.-3 -

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Synthesis and structure–activity relationship of N-acyl-Gly-, N-acyl-Sar- and N-blocked-boroPro inhibitors of FAP, DPP4, and POP

Cited by 47 publications

References 12 publications

Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010

Seprase: An overview of an important matrix serine protease

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