Synthesis and structure–activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7

Hu, Yi; Ma, Liming; Wu, Min; Wong, Melissa S.; Li, Bei; Corral, Sergio; Yu, Zhizhou; Nomanbhoy, Tyzoon; Alemayehu, Senaiet; Fuller, Stacy R.; Rosenblum, Jonathan S.; Rozenkrants, Natasha; Minimo, Lauro; Ripka, William C.; Szardenings, Anna Katrin; Kozarich, John W.; Shreder, Kevin

doi:10.1016/j.bmcl.2005.06.075

Cited by 31 publications

(21 citation statements)

References 8 publications

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“…Most research effort in the domain of FAP-inhibitor discovery to date has been centered around pyrrolidine-2-boronic acid derivatives. 15,16 These compounds in general also display significant affinity for one or several DPPs. 15,16 The most representative of this class, Val-boroPro (Talabostat, PT-100) 1 has reached phase II clinical trials (Table 1).…”

Section: * S Supporting Informationmentioning

confidence: 99%

“…15,16 These compounds in general also display significant affinity for one or several DPPs. 15,16 The most representative of this class, Val-boroPro (Talabostat, PT-100) 1 has reached phase II clinical trials (Table 1). It was evaluated as a therapeutic drug for, among others, metastatic kidney cancer, pancreatic adenocarcinoma, nonsmall cell lung cancer, and chronic lymphocytary leukemia (Figure 1).…”

Section: * S Supporting Informationmentioning

confidence: 99%

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Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Jansen

Heirbaut

Cheng

et al. 2013

ACS Med. Chem. Lett.

184

147

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Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp 2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10 3 ) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

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Section: * S Supporting Informationmentioning

confidence: 99%

Section: * S Supporting Informationmentioning

confidence: 99%

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Jansen

Heirbaut

Cheng

et al. 2013

ACS Med. Chem. Lett.

184

147

View full text Add to dashboard Cite

show abstract

“…Also, the widespread expression of many of these enzymes is likely to limit their potential as therapeutic targets. In contrast, FAP (also called FAPα or seprase) has recently gained attention as a potential target, due to its tightly regulated expression in the tumor stroma and structurally defined proteolytic activity (7)(8)(9)(10)(11); however, its function in tumors is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Santos

Jung²,

Aziz³

et al. 2009

J. Clin. Invest.

378

357

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Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelialderived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-ras G12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-ras G12D -driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell-mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

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“…ValboroPro displayed IC 50 values in the nanomolar range to several prolyl peptidases [ 24 ]. The introduction of a blocked N terminus in the dipeptidyl boronic acid structure led to novel inhibitors that were evaluated regarding binding affinity and selectivity [ 25 , 26 , 27 , 28 , 29 ] with the advantage of impeded intra-molecular cyclization reactions mediated by the electrophilic boron and an increased selectivity over DPPs that lack endopeptidase activity [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Radiolabeled Boronic Acid-Based FAP Inhibitor MIP-1232 for Atherosclerotic Plaque Imaging

et al. 2015

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Research towards the non-invasive imaging of atherosclerotic plaques is of high clinical priority as early recognition of vulnerable plaques may reduce the incidence of cardiovascular events. The fibroblast activation protein alpha (FAP) was recently proposed as inflammation-induced protease involved in the process of plaque vulnerability. In this study, FAP mRNA and protein levels were investigated by quantitative polymerase chain reaction and immunohistochemistry, respectively, in human endarterectomized carotid plaques. A published boronic-acid based FAP inhibitor, MIP-1232, was synthetized and radiolabeled with iodine-125. The potential of this radiotracer to image plaques was evaluated by in vitro autoradiography with human carotid plaques. Specificity was assessed with a xenograft with high and one with low FAP level, grown in mice. Target expression analyses revealed a moderately higher protein level in atherosclerotic plaques than normal arteries correlating with plaque vulnerability. No difference in expression was determined on mRNA level. The radiotracer was successfully produced and accumulated strongly in the FAP-positive SK-Mel-187 melanoma xenograft in vitro while accumulation was negligible in an NCI-H69 xenograft with low FAP levels. Binding of the tracer to endarterectomized tissue was similar in plaques and normal arteries, hampering its use for atherosclerosis imaging.

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Synthesis and structure–activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7

Cited by 31 publications

References 8 publications

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Evaluation of the Radiolabeled Boronic Acid-Based FAP Inhibitor MIP-1232 for Atherosclerotic Plaque Imaging

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