talabostat   Click here for help

GtoPdb Ligand ID: 9892

Synonyms: compound 1 [PMID: 18783201] | PT-100 | PT100 | Val-boro-pro | Val-boroPro
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Talabostat (PT-100, or Val-boroPro) is a compound with potent anti-tumour activity. It is a non-selective inhibitor of post-proline-cleaving serine proteases. Talabostat activates macrophages at least in part via inhibition of the serine peptidase, fibroblast activation protein (FAP) , an action that has been examined for anti-cancer utility [2,4-5] and anti-fibrotic potential [3]. More recently talabostat has been reported as an inhibitor of the cytosolic serine dipeptidyl peptidases Dpp8 and Dpp9, and that inhibition of these related enzymes stimulates the immune system via the selective promotion of proinflammatory cell death (pyroptosis) of monocytes and macrophages [6]. This process involves Dpp8/9-induced activation of the NOD-like pattern recognition receptor NLRP1, a protein that acts as an inflammasome sensor, followed by activation of pro-caspase-1 and eventually to pyroptosis [7].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 3
Rotatable bonds 4
Topological polar surface area 86.79
Molecular weight 214.15
XLogP -0.57
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES CC(C(C(=O)N1CCCC1B(O)O)N)C
Isomeric SMILES CC([C@@H](C(=O)N1CCC[C@H]1B(O)O)N)C
InChI InChI=1S/C9H19BN2O3/c1-6(2)8(11)9(13)12-5-3-4-7(12)10(14)15/h6-8,14-15H,3-5,11H2,1-2H3/t7-,8-/m0/s1
InChI Key FKCMADOPPWWGNZ-YUMQZZPRSA-N
References
1. Connolly BA, Sanford DG, Chiluwal AK, Healey SE, Peters DE, Dimare MT, Wu W, Liu Y, Maw H, Zhou Y et al.. (2008)
Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety.
J Med Chem, 51 (19): 6005-13. [PMID:18783201]
2. Eager RM, Cunningham CC, Senzer NN, Stephenson Jr J, Anthony SP, O'Day SJ, Frenette G, Pavlick AC, Jones B, Uprichard M et al.. (2009)
Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.
BMC Cancer, 9: 263. [PMID:19643020]
3. Egger C, Cannet C, Gérard C, Suply T, Ksiazek I, Jarman E, Beckmann N. (2017)
Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis.
Eur J Pharmacol, 809: 64-72. [PMID:28506908]
4. Li M, Li M, Yin T, Shi H, Wen Y, Zhang B, Chen M, Xu G, Ren K, Wei Y. (2016)
Targeting of cancer‑associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment.
Mol Med Rep, 13 (3): 2476-84. [PMID:26846566]
5. Narra K, Mullins SR, Lee HO, Strzemkowski-Brun B, Magalong K, Christiansen VJ, McKee PA, Egleston B, Cohen SJ, Weiner LM et al.. (2007)
Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer.
Cancer Biol Ther, 6 (11): 1691-9. [PMID:18032930]
6. Okondo MC, Johnson DC, Sridharan R, Go EB, Chui AJ, Wang MS, Poplawski SE, Wu W, Liu Y, Lai JH et al.. (2017)
DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis.
Nat Chem Biol, 13 (1): 46-53. [PMID:27820798]
7. Okondo MC, Rao SD, Taabazuing CY, Chui AJ, Poplawski SE, Johnson DC, Bachovchin DA. (2018)
Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome.
Cell Chem Biol, 25 (3): 262-267.e5. [PMID:29396289]