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Chemical Compound Review

TPCK     N-[(2S)-4-chloro-3-oxo-1- phenyl-butan-2...

Synonyms: Tos-Phe-CH2Cl, Lopac-T-4376, CHEMBL60718, CHEBI:9642, BSPBio_001541, ...
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Disease relevance of TPCK

  • Treatment of mouse adenocarcinoma cell line CSML-100 with both synthetic (TPCK or PDTC) or natural (I(kappaB)-alpha) NF-kappaB inhibitors caused apoptotic death [1].
  • The complete amino acid sequences of both toxins, each containing 64 amino acid residues, were determined by the automatic sequencing of reduced and S-carboxymethylated toxins and their peptides, obtained after cleavage with TPCK-treated trypsin and Staphylococcus aureus V8 protease, respectively [2].
  • STUDY DESIGN: NA cells, an oral cavity squamous cell cancer with high NF-KappaB activity, were cultured with biochemical NF-KappaB inhibitors TPCK and Calpain I inhibitor, as well as specific NF-KappaB antisense oligonucleotides [3].

High impact information on TPCK

  • Furthermore, a blockade of NF-kappaB activation by PDTC and TPCK markedly reduced the IL-1beta- or TNF-alpha-induced chemokine gene expression [4].
  • The dose-response and the time-course of the inhibitor, however, indicated that the site of action of TPCK for NF-kappa B activation and for DNA fragmentation are quite distinct [5].
  • The addition of TPCK to cells 30 minutes after TNF treatment completely inhibited the cytokine action, indicating that TPCK-sensitive proteases are not involved in the early stages of signal transduction [5].
  • Death of CSML100 cells in the presence of high concentration TPCK was not accompanied with significant changes in c-myc activity but strongly correlated with rapid decrease in p53 level [1].
  • Low doses of TPCK were harmless for CSML100 cells but sensitized them to TNF-induced apoptosis [1].

Biological context of TPCK

  • Therefore, we conclude that TNF activates two distinct TPCK-sensitive pathways, one leading to apoptosis and the other to NF-kappa B activation [5].
  • The redox-sensitive transcription factor NF-kappaB was recruited in hemin-induced upregulation of MCP-1 because two different compounds that abrogate the activation of NF-kappaB (TPCK and BAY 11-7082) completely blocked hemin-induced upregulation of MCP-1 mRNA [6].
  • The TPCK reactive site is at Cys-82 [7].
  • Thus TPCK pretreatment before buprenorphine hydrochloride administration induced apoptosis-independent cell death, presumably necrosis, in NG108-15 cells [8].
  • Esterase inhibitors SBTI and TPCK had no effect on the formation of platelet-target cell adhesion but inhibited the cytotoxicity of unstimulated platelets [9].

Anatomical context of TPCK


Associations of TPCK with other chemical compounds

  • Treatment of the supernatant with a serine protease inhibitor, N-tosyl-L-phenylala-nylchloromethyl ketone (TPCK), abolished the DNA fragmenting activity [15].
  • In the present study, we report the presence of two distinct CaaX-proteolytic activities in membrane extracts from Caenorhabditis elegans, which are sensitive to EDTA and Tos-Phe-CH(2)Cl (tosylphenylalanylchloromethane; 'TPCK') respectively [16].
  • Conversely, the tryptic-type protease inhibitor, TLCK (N-alpha-p-tosyl-lysine chloromethylketone), which structurally is very similar to TPCK, had no effect on IL2 synthesis [17].
  • The chymotrypsin inhibitors TPCK and chymostatin and the chymotrypsin substrates ATEE, BTEE (N-Benzoyl-L-Tyrosine Ethyl Ester), Succinyl-Ala-Ala-Phe-7-Amido-4-Methyl-Coumarin (Suc-Ala-Ala-Phe-AMC), and Succinyl-Leu-Leu-Val-Tyr-7-Amido-4-Methyl-Coumarin (Suc-Leu-Leu-Val-Tyr-AMC) inhibited the human follicular fluid-induced acrosome reaction [12].
  • None of the inhibitors was able to substantially reduce proteolysis of beta-LPH, as was the case with amastatin, APMSF, and TPCK for beta-EPH [18].

Gene context of TPCK

  • Inhibition of NFkappaB with TPCK reduced COX-2 but not COX-1 gene expression and decreased PGE2 production by LPS-stimulated Mphi [19].
  • Interestingly, the OR current induced by Tat was largely prevented by two inhibitors of the transcription factor NF-kappaB, TPCK and SN50, which suggests an involvement of NF-kappaB in the effect of the viral protein [20].
  • Whereas TPCK inhibits phosphorylation of I kappa B and, consequently, activation of NF-kappa B, it markedly enhances the activity of JNK, the MAP kinase-related kinase that phosphorylates the transactivation domain of c-Jun [21].
  • Another biological effect of tosylphenylalanylchloromethane (TPCK): it prevents p47phox phosphorylation and translocation upon neutrophil stimulation [22].
  • In contrast, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors TPCK and TLCK as well as by caspase inhibitors DEVD and zVAD [23].

Analytical, diagnostic and therapeutic context of TPCK

  • The purified cytochrome c derivatives were digested with TPCK treated trypsin and the resulting peptides were separated by reverse phase HPLC [24].
  • METHOD: Changes and subcellular loca-lization of IkappaB-alpha were observed by fluorescence microscopy, expression and degradation of IkappaB-alpha protein with N-tosyl-L-phenylalanylchloromethyl ketone (TPCK protease inhibitor) blocking test and apoptosis of U937 cell by flow cytometry [25].


  1. High constitutive level of NF-kappaB is crucial for viability of adenocarcinoma cells. Smirnov, A.S., Ruzov, A.S., Budanov, A.V., Prokhortchouk, A.V., Ivanov, A.V., Prokhortchouk, E.B. Cell Death Differ. (2001) [Pubmed]
  2. Two neurotoxins (BmK I and BmK II) from the venom of the scorpion Buthus martensi Karsch: purification, amino acid sequences and assessment of specific activity. Ji, Y.H., Mansuelle, P., Terakawa, S., Kopeyan, C., Yanaihara, N., Hsu, K., Rochat, H. Toxicon (1996) [Pubmed]
  3. NF-Kappa-B downregulation strategies in head and neck cancer treatment. Patel, A., Miller, L., Ahmed, K., Ondrey, F. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. (2004) [Pubmed]
  4. Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Andoh, A., Takaya, H., Saotome, T., Shimada, M., Hata, K., Araki, Y., Nakamura, F., Shintani, Y., Fujiyama, Y., Bamba, T. Gastroenterology (2000) [Pubmed]
  5. Protease inhibitors differentially regulate tumor necrosis factor-induced apoptosis, nuclear factor-kappa B activation, cytotoxicity, and differentiation. Higuchi, M., Singh, S., Chan, H., Aggarwal, B.B. Blood (1995) [Pubmed]
  6. Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms. Kanakiriya, S.K., Croatt, A.J., Haggard, J.J., Ingelfinger, J.R., Tang, S.S., Alam, J., Nath, K.A. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  7. Identification of the N-tosyl-L-phenylalanyl chloromethylketone modification site in Thermus thermophilus elongation factor Tu. Peter, M.E., Brockmöller, J., Jonák, J., Sprinzl, M. FEBS Lett. (1989) [Pubmed]
  8. Buprenorphine hydrochloride induces apoptosis in NG108-15 nerve cells. Kugawa, F., Arae, K., Ueno, A., Aoki, M. Eur. J. Pharmacol. (1998) [Pubmed]
  9. Cytotoxicity of unstimulated and thrombin-activated platelets to human tumour cells. Sagawa, T., Tominaga, A., Kodama, T., Okada, M. Immunology (1993) [Pubmed]
  10. Identification of radiation-specific responses from gene expression profile. Park, W.Y., Hwang, C.I., Im, C.N., Kang, M.J., Woo, J.H., Kim, J.H., Kim, Y.S., Kim, J.H., Kim, H., Kim, K.A., Yu, H.J., Lee, S.J., Lee, Y.S., Seo, J.S. Oncogene (2002) [Pubmed]
  11. A biphasic role of nuclear transcription factor (NF)-kappaB in the islet beta-cell apoptosis induced by interleukin (IL)-1beta. Papaccio, G., Graziano, A., D'Aquino, R., Valiante, S., Naro, F. J. Cell. Physiol. (2005) [Pubmed]
  12. Evidences for the presence of chymotrypsin-like activity in human spermatozoa with a role in the acrosome reaction. Morales, P., Socias, T., Cortez, J., Llanos, M.N. Mol. Reprod. Dev. (1994) [Pubmed]
  13. Human lymphokine-activated killer (LAK) cells: III. Effect of L-phenylalanine methyl ester on LAK cell activation from human peripheral blood mononuclear cells: possible protease involvement of monocytes, natural killer cells and LAK cells. Leung, K.H. Cancer Immunol. Immunother. (1991) [Pubmed]
  14. Antibody-dependent tumour cytolysis by human neutrophils: effect of synthetic serine esterase inhibitors and substrates. Dallegri, F., Frumento, G., Ballestrero, A., Goretti, R., Torresin, A., Patrone, F. Immunology (1987) [Pubmed]
  15. Role of serine and ICE-like proteases in induction of apoptosis by etoposide in human leukemia HL-60 cells. Yoshida, A., Takauji, R., Inuzuka, M., Ueda, T., Nakamura, T. Leukemia (1996) [Pubmed]
  16. Identification, functional expression and enzymic analysis of two distinct CaaX proteases from Caenorhabditis elegans. Cadiñanos, J., Schmidt, W.K., Fueyo, A., Varela, I., López-Otín, C., Freije, J.M. Biochem. J. (2003) [Pubmed]
  17. A chymotryptic-type protease inhibitor decreases interleukin 2 synthesis and induces prostaglandin production in Jurkat T cells. Auberger, P., Didier, M., Didier, J., Aussel, C., Fehlmann, M. Cell. Signal. (1989) [Pubmed]
  18. Proopiomelanocorticotropin (POMC) peptides and lipoprotein lipase activity in vitro. Eichhorn, P., Schwandt, P., Richter, W.O. Peptides (1995) [Pubmed]
  19. Regulation of macrophage eicosanoid generation is dependent on nuclear factor kappaB. Lo, C.J., Cryer, H.G., Fu, M., Lo, F.R. The Journal of trauma. (1998) [Pubmed]
  20. Altered outward-rectifying K(+) current reveals microglial activation induced by HIV-1 Tat protein. Visentin, S., Renzi, M., Levi, G. Glia (2001) [Pubmed]
  21. Costimulation requirement for AP-1 and NF-kappa B transcription factor activation in T cells. Jung, S., Yaron, A., Alkalay, I., Hatzubai, A., Avraham, A., Ben-Neriah, Y. Ann. N. Y. Acad. Sci. (1995) [Pubmed]
  22. Another biological effect of tosylphenylalanylchloromethane (TPCK): it prevents p47phox phosphorylation and translocation upon neutrophil stimulation. Gillibert, M., Dehry, Z., Terrier, M., El Benna, J., Lederer, F. Biochem. J. (2005) [Pubmed]
  23. A novel hydroxamic acid compound, BMD188, demonstrates anti-prostate cancer effects by inducing apoptosis. I: In vitro studies. Li, L., Zhu, Z., Joshi, B., Porter, A.T., Tang, D.G. Anticancer Res. (1999) [Pubmed]
  24. Preparation and electron paramagnetic resonance characterization of spin labeled monoderivatives of horse cytochrome c. Turyna, B., Osyczka, A., Kostrzewa, A., Blicharski, W., Enghild, J.J., Froncisz, W. Biochim. Biophys. Acta (1998) [Pubmed]
  25. Study on the expression of IkappaB-alpha protein in TNF-alpha induced apoptosis of U937 cells. Chen, W., Peng, G., Tang, A., Wang, K., Zhou, M., Wang, L. Zhonghua Xue Ye Xue Za Zhi (2002) [Pubmed]
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