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

Melting point:

>160°C (dec.)

storage temp. 

under inert gas (nitrogen or Argon) at 2–8 °C

solubility 

Soluble in DMSO (up to at least 25 mg/ml)

form 

solid

color 

White

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.

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

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

Treatment of cancer; hematopoetic stimulant.

Uses

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

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

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