Talabostat (PT100)
(Synonyms: [(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸,Val-boroPro; PT100) 目录号 : GC33853Talabostat (PT100)是一种口服活性的二肽基肽酶IV DPP-IV IC50 < 4 nM的非选择性抑制剂;Ki = 0.18 nM,临床首个成纤维细胞活化蛋白FAP抑制剂IC50= 560 nM,抑制DPP 8/9的IC50= 4/11 nM;Ki = 1.5/0.76 nM,脯氨酸内肽酶QPP IC50= 310 nM, DPP2等DASH家族酶。
Cas No.:149682-77-9
Sample solution is provided at 25 µL, 10mM.
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Animal experiment: | Mice: BLM (0.5mg/kg/day) is administered on days -7, -6, -5, -2, -1, 0 in the nostrils of male mice. Talabostat (40 µg/mouse) or vehicle (0.9% NaCl) is dosed per os twice daily from day 1-14. MRI is performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals are euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses[4]. |
References: [1]. Lankas GR, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005 Oct;54(10):2988-94. |
Talabostat (Val-boroPro, PT-100) is a dipeptidyl peptidase inhibitor with IC50 values of <4 nM, 4 nM, 11 nM, 310 nM, 560 nM and 390 nM for DPP-IV, DPP8, DPP9, QPP, FAP and PEP respectively. It has antineoplastic and hematopoiesis- stimulating activities.
In vitro, talabostat upregulates cytokines/chemokines in human bone marrow stromal cells[2]. Talabostat (Val-boroPro) induces monocytes and macrophage cell death. Val-boroPro induced pyroptosis requires caspase-1[4].
Talabostat has been shown to produce potent antitumor effects when administered orally in multiple mouse tumor models. Val-boroPro mediates complete tumor regression via a novel mechanism that requires more rapid DC trafficking and subsequent acceleration of T cell priming[3]. In tumor stroma, talabostat can directly target FAP expressed by reactive fibroblasts. Talabostat stimulates innate and adaptive immune responses against tumors involving transcriptional upregulation of cytokines and chemokines[2]. Val-boroPro is known to stimulate the transcriptional upregulation several cytokines, including IL-1β, IL-6, G-CSF, and CXCL1/KC, in both tumors and tumor-draining lymph nodes, and to increase the mouse serum protein levels of several of these cytokines, including G-CSF and CXCL1/KC[4].
[1] Lankas GR, et al. Diabetes. 2005, 54(10):2988-94. [2] Michael Jesson, et al. American Association for Cancer Research. 2007, 67(9):Supplement. [3] Walsh MP, et al. PLoS One. 2013, 8(3):e58860.
Cas No. | 149682-77-9 | SDF | |
别名 | [(2R)-1-[(2S)-2-氨基-3-甲基丁酰基]吡咯烷-2-基]硼酸,Val-boroPro; PT100 | ||
Canonical SMILES | CC(C)[C@H](N)C(N1[C@H](B(O)O)CCC1)=O | ||
分子式 | C9H19BN2O3 | 分子量 | 214.07 |
溶解度 | DMSO : ≥ 40 mg/mL (186.85 mM) | 储存条件 | Store at -20°C |
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10 mM | 0.4671 mL | 2.3357 mL | 4.6714 mL |
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Precise Diabetic Wound Therapy: PLS Nanospheres Eliminate Senescent Cells via DPP4 Targeting and PARP1 Activation
Adv Sci (Weinh) 2022 Jan;9(1):e2104128.PMID:34738744DOI:10.1002/advs.202104128.
Diabetic ulcers, a difficult problem faced by clinicians, are strongly associated with an increase in cellular senescence. Few empirical studies have focused on exploring a targeted strategy to cure diabetic wounds by eliminating senescent fibroblasts (SFs) and reducing side effects. In this study, poly-l-lysine/sodium alginate (PLS) is modified with Talabostat (PT100) and encapsulates a PARP1 plasmid (PARP1@PLS-PT100) for delivery to target the dipeptidyl peptidase 4 (DPP4) receptor and eliminate SFs. PARP1@PLS-PT100 releases encapsulated plasmids, displaying high selectivity for SFs over normal fibroblasts by targeting the DPP4 receptor, decreasing senescence-associated secretory phenotypes (SASPs), and stimulating the secretion of anti-inflammatory factors. Furthermore, the increased apoptosis of SFs and the disappearance of cellular senescence alleviates SASPs, accelerates re-epithelialization and collagen deposition, and significantly induces macrophage M2 polarization, which mediates tissue repair and the inflammatory response. This innovative strategy has revealed the previously undefined role of PARP1@PLS-PT100 in promoting diabetic wound healing, suggesting its therapeutic potential in refractory wound repair.
DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis
Nat Chem Biol 2017 Jan;13(1):46-53.PMID:27820798DOI:10.1038/nchembio.2229.
Val-boroPro (Talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted substantial interest as a potential anticancer agent, reaching phase 3 trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the pro-protein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identify what is to our knowledge the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.
Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis
Eur J Pharmacol 2017 Aug 15;809:64-72.PMID:28506908DOI:10.1016/j.ejphar.2017.05.022.
Bleomycin (BLM) induced lung injury is detectable in C57BL/6 mice using magnetic resonance imaging (MRI). We investigated the effects of the fibroblast activation protein (FAP) inhibitor, PT100, in this model. BLM (0.5mg/kg/day) was administered on days -7, -6, -5, -2, -1, 0 in the nostrils of male mice. PT100 (40µg/mouse) or vehicle (0.9%NaCl) was dosed per os twice daily from day 1-14. MRI was performed before BLM and at days 0, 7 and 14. After the last MRI acquisition, animals were euthanised and the lungs harvested for histological and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. As evidenced longitudinally by MRI, the BLM-elicited lesions in the lungs of vehicle-treated mice progressed over time. In contrast, responses elicited by BLM did not progress in animals receiving PT100. Histology demonstrated significant less fibrosis in PT100- than in vehicle-treated, BLM-challenged mice. Significant correlation (R=0.91, P<0.001, N=24) was found between the volumes of BLM-induced lesions detected in vivo by MRI and the collagen content determined histologically (picrosirius staining). FAP was overexpressed in the lungs of BLM-challenged mice. Upon PT100 treatment, FAP expression was reduced. Significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs of PT100- compared to vehicle-treated mice were also revealed by qRT-PCR. The IBA-1 level determined histologically was higher in the lungs of PT100- compared to vehicle-treated mice. Taken together, these observations suggest that treatment with PT100 in this murine model of pulmonary fibrosis had an anti-fibro-proliferative effect and increased macrophage activation.
Phase II trial of Talabostat and docetaxel in advanced non-small cell lung cancer
Clin Oncol (R Coll Radiol) 2009 Aug;21(6):464-72.PMID:19501491DOI:10.1016/j.clon.2009.04.007.
Aims: Currently available therapies do improve survival in advanced stage non-small cell lung cancer (NSCLC), but only to a limited degree. Talabostat mesilate (PT-100) is an orally available amino boronic dipeptide that specifically inhibits dipeptidyl peptidases (including fibroblast activation protein) and enhances an immune response. The aim of this study was to determine the efficacy and safety of Talabostat in NSCLC patients. Materials and methods: A phase II trial was conducted to evaluate Talabostat in combination with docetaxel in patients with advanced NSCLC after failure of previous platinum-based chemotherapy. In total, 42 patients were enrolled. Results: Talabostat was well tolerated. Two patients achieved a partial response and one achieved a complete response. Conclusion: There was no evidence that Talabostat enhanced the clinical activity of docetaxel in patients with NSCLC.
Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome
Cell Chem Biol 2018 Mar 15;25(3):262-267.e5.PMID:29396289DOI:10.1016/j.chembiol.2017.12.013.
Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that Dpp8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system.