[(2R)-1-[(2S)-2-Amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid mesylate

Description

Talabostat is a non-selective inhibitor of dipeptidyl peptidases (DPPs), including DPP-4, DPP-7, DPP-8, DPP-9, fibroblast activation protein (FAP), and prolyl endopeptidase (PREP; IC₅₀s = >4, 310, 4, 11, 560, and 390 nM, respectively). It inhibits proliferation of superantigen-stimulated human peripheral blood mononuclear cells (PBMCs; IC₅₀ = ~10 nM). Talabostat (5 μg twice per day) increases expression of a variety of cytokines, including those encoding IL-1β, IL-6, and G-CSF, and chemokines in tumors and tumor-draining lymph nodes in a WEHI-164 fibrosarcoma mouse model. It reduces tumor growth in WEHI-164, MM45T.Sp, and MM52.T fibrosarcoma, EL-4 and A20/2J lymphoma, B16/F10 melanoma, and P815 mastocytoma syngeneic mouse models. Talabostat also increases the efficacy of the antitumor antibodies rituximab and trastuzumab in Namalwa B cell lymphoma and LS180 colon carcinoma mouse xenograft models, respectively.

Uses

Talabostat Mesylate can be used in biological study and pharmacological activity of treatment of cancer using immunomodulation.

Uses

Treatment of cancer; hematopoetic stimulant.

General Description

A prolineboronic acid-based broad-spectrum DDP IV activity and/or structural homologue (DASH) family dipeptidyl peptidases inhibitor that converts in solution between the protonated active form and a cyclized inactive form due to a reversible intramolecular B-N dative bond formation of the non-protonated Val-boroPro (k_inact = 6.4 x 10^--4 s^- and k_cyc = 6.4 x 10^-5 s^- at pH 7.8). Although equilibrium favors cyclization at basic pH, high affinity binding (k_on & k_off toward CD26 at pH 7.8 = 5.02 x 10⁶ M^-s^- and 77.8 x 10^-6 s^-, respectively) drives the equilibrium away from cyclization and traps the active form in enzyme-bound state with prolonged incubation. Reported to inhibit DPP7/DPPII/QPP (IC₅₀/[Substrate]/rxn time at pH 5.5 = 15 nM/500 μM Lys-Pro-MNA/1 h & 310 nM/50 μM Nle-Pro-AMC/15 min), CD26/DPPIV (IC₅₀ = 26 nM; 500 μM Ala-Pro-MNA for 1 h at pH 7.8), fibroblast activation protein/FAP (IC₅₀ = 40 nM; 250 μM Ala-Pro-AFC at pH 2.0), DPP8 (IC₅₀ = 4 nM; 100 μM Ala-Pro-AFC for 15 min at pH 8.0), DDP9 (IC₅₀ = 11 nM; 100 μM Gly-Pro-AMC for 30 min at pH 7.4) with little potency against 9 other proteases (IC₅₀ >100 μM; aminopeptidase P, chymoptrypsin, leukocyte elastase, plasma kallikrein, plasmin, prolidase, thrombin, trypsin, tryptase), while contradictory reports regarding prolyl endopeptidase/PEP/PREP inhibition exist (e.g. IC₅₀ = 390 nM/50 μM Z-Gly-Pro-AMC/pH 7.5/30 min vs. 25 μM/500 μM Z-Gly-Pro-MNA/pH 7.8/60 min). Shown to promote the propagation of human BM CD34⁺ cells by stimulating stromal cells cytokine production in vitro (min EC 0.1 nM) and display hematopoietic stimulatory effect in mice in vivo (min ED 2 μg/mouse/12 h; p.o.). Although orally available in mice and rats, caution must be taken not to exceed toxicity levels (MTD = 25 μg/mL using Sprague-Dawley rats; LD₅₀ ~0.5 mg/mL in 24 survival test using Fisher rats; p.o.) for in vivo studies.

Biochem/physiol Actions

Cell permeable: yes

in vitro

by the cleavage of n-terminal xaa-pro or xaa-ala residues, talabostat blocks dipeptidyl peptidases, such as fibroblast activation protein (fap), resulting in inducing the production of cytokine and chemokine (besides specific t-cell immunity and t-cell-dependent activity). this agent may also induce the production of colony stimulating factors, for instance, granulocyte colony stimulating factor (g-csf), resulting in the inducement of hematopoiesis. dipeptidyl peptidases are referred to the activation of polypeptide hormones and chemokines.

IC 50

1 nm

storage

Store at -20°C

References

1) Lankas et al. (2005) Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes; Diabetes 54 2988 2) Adams et al. (2004) PT-100,a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism; Cancer Res. 64 5471 3) Walsh et al. (2013) Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors; PLoS One 8 e58860 4) Okondo et al. (2017) DPP8/9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis; Nat. Chem. Biol. 13 46 5) Okondo et al. (2018) Inhibition of DPP8/9 Activates the Nlrp1b Inflammasome; Cell Chem. Biol. 25 1