Talabostat (PT100) is an orally active and non-selective inhibitor of dipeptidyl peptidase IV (DPP-IV) (IC50 < 4 nM; Ki = 0.18 nM) and the first clinical inhibitor of fibroblast activation protein (FAP) (IC50= 560 nM), inhibiting DPP 8/9 (IC50= 4/11 nM; Ki = 1.5/0.76 nM), prolyl endopeptidase (QPP) (IC50= 310 nM), DPP2, and other DASH family enzymes[1]. Due to its inhibitory action on these proteases, the mechanism of action of Talabostat (PT100) involves the inhibition of protease activity, thereby affecting the tumor microenvironment, immune cell activity, and inflammatory responses[2]. Talabostat (PT100) is also known to stimulate hematopoiesis.
In vitro, Talabostat (PT100) at concentrations ranging from 30 pg/ml to 30 μg/ml when added to the culture medium, can induce tumor regression and rejection in WEHI 164 fibrosarcoma and EL 4 and A20/2 J lymphoma models[1]. Talabostat (PT100) (2μM, 24h) can induce the active form of caspase-1, which can efficiently cleave substrates mediating pyroptosis but not effectively cleave IL-1β or the tetrapeptide Ac-WEHD-AFC[4]. In tumors and tumor-draining lymph nodes, Talabostat (PT100) stimulates the transcriptional upregulation of various cytokines such as IL-1β, IL-6, G-CSF, and CXCL1/KC[4].
In vivo, Talabostat (PT100) significantly inhibits the extraneous growth of tumors such as B16-F10, WEHI 164, and EL 4 tumor cells in mice through delayed oral administration (5–40 μg, twice daily, approximately 8 hours apart) [3].
References:
[1] Connolly BA, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potencyand in vivo efficacy and safety. J Med Chem. 2008 Oct 9;51(19):6005-13.
[2] 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.
[3] Adams S, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004 Aug 1;64(15):5471-80.
[4] Okondo M C , Johnson D C , Sridharan R ,et al.DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis[J].Nature Chemical Biology, 2017 Jan; 13(1): 46–53.
Talabostat (PT100)是一种口服活性和非选择性二肽基肽酶IV（DPP-IV）抑制剂(IC50 < 4 nM; Ki = 0.18 nM)和成纤维细胞活化蛋白(FAP)的第一种临床抑制剂(IC50 = 560 nM)，抑制DPP 8/9(IC50= 4/11 nM; Ki = 1.5/0.76 nM)，静止细胞脯氨酸二肽酶(QPP)( IC50= 310 nM)，DPP 2和其他一些DASH家族酶[1]。由于其对这些蛋白酶的抑制作用，Talabostat (PT100)的作用机制涉及抑制蛋白酶活性，进而影响肿瘤微环境、免疫细胞活性以及炎症反应[2]。Talabostat (PT100)还可作用于刺激造血。
在体外，Talabostat (PT100)以30 pg/ml至30 μg/ml的浓度加入培养基中，在WEHI 164纤维肉瘤和EL 4和A20/2 J淋巴瘤模型中可引起肿瘤消退和排斥[3]。Talabostat (PT100) (2μM, 24h) 可以诱导活性形式的胱天蛋白酶原-1，其可以充分切割介导焦亡的底物，但不能有效切割IL-1β或四肽Ac-WEHD-AFC[4]。在肿瘤和肿瘤引流淋巴结中，Talabostat (PT100)可刺激多种细胞因子的转录上调，如IL-1β、IL-6、G-CSF和CXCL1/KC[4]。
在体内，Talabostat (PT100)通过延迟口服施用(5–40 μg，每日两次，间隔约8小时)，在接种有B16-F10、WEHI 164和EL 4肿瘤细胞的小鼠中，显著抑制了这些肿瘤的额外生长[3]。