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Chemical Compound Review

CA-074     (2S)-1-[(2S,3S)-3-methyl-2- [[(3S)-3...

Synonyms: LS-172894, CA 074, AC1L3U3Y, C18H29N3O6, 134448-10-5
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Disease relevance of CA 074

  • These stimulators of secretion of procathepsin L enhanced bone pit formation, which was inhibited by E-64, but not by CA-074, a specific inhibitor of cathepsin B. Procathepsin L may thus participate in the process of bone collagenolysis during bone resorption [1].
  • Administration of CA-074, a cathepsin B inhibitor, suppresses the response to exogenous antigens, such as hepatitis B virus antigen, ovalbumin and Leishmania major antigen, and induces switching of the helper T cell responses from Th-2 to Th-1 of CD4+ T cells, thereby downregulating the production of IgE and IgG1 [2].
  • Cathepsin inhibition was investigated in the dextran-sulphate-sodium (DSS) colitis model in mice with application of pepstatin A (CTSD inhibitor), CA-074 (CTSB inhibitor) and Z-Phe-Tyr-aldehyde (CTSL inhibitor) [3].

High impact information on CA 074

  • Moreover, CA-074, a specific cathepsin B inhibitor, also abolished the neurotoxic effects caused by Abeta42-activated BV2 cells [4].
  • Co-treatment of cultures with the cathepsin B inhibitors CA-074 or Z-FA-FMK suppressed the cytostatic effects of TPA and activation of pro-uPA [5].
  • Pharmacological inhibition of cat B in catB(+/+) mice with L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-L-isoleucyl-L-proline (CA-074 Me) also reduced TNF-alpha-induced liver damage [6].
  • Serum calcium in rats placed on a low calcium diet was decreased by treatment of E-64 or cystatin A, but not by CA-074 [7].
  • Administration of compound CA-074 or pepstatinasialofetuin to rats caused only a slight shift of the lysosomal density and no increase in sequestered enzymes in the autolysosomal fraction, although cathepsin B or D activity in the liver was markedly inhibited [8].

Associations of CA 074 with other chemical compounds

  • Administration of cathepsin B inhibitors, E-64, CA-074 and vitamin B6, caused the strong suppression of the Th-2 type immune responses [9].
  • We have established a new differential assay method for cathepsin L-type proteinases using specific inhibitors, E-64 for all cysteine proteinases, CA-074 for cathepsin B, and PLCPI for cathepsin L-type proteinases with Z-Phe-Arg-MCA as the substrate [10].

Gene context of CA 074

  • Assessment of cathepsin L activity by use of the inhibitor CA-074 compared to cathepsin B activity in human lung tumor tissue [11].
  • In contrast, exposure of these cells to the parental compound CA-074 leads to the selective inhibition of endogenous cathepsin B, while intracellular cathepsin L remains unaffected [12].
  • To evaluate the contribution of individual cathepsins, specific inhibitors have been developed based on cathepsin tertiary structures: CA-074 for cathepsin B, CLIK-148 and -195 for cathepsin L, CLIK-60 for cathepsin S [2].
  • 8. This activation was not inhibited by CA-074, a specific inhibitor of cathepsin B, but was strongly inhibited by CLIK-066 and CLIK-181, specific inhibitors of cathepsin L. The inhibitory effect of CLIK-060, a specific inhibitor of cathepsin S, was very weak [13].
  • The cathepsin-B-selective E-64 derivative, CA-074, inhibited penetration of Matrigel by SCC-VII cells to the same extent, indicating a major role for this particular lysosomal enzyme in extracellular-matrix degradation during squamous-carcinoma-cell invasion [14].

Analytical, diagnostic and therapeutic context of CA 074


  1. Secretion and processing mechanisms of procathepsin L in bone resorption. Kakegawa, H., Tagami, K., Ohba, Y., Sumitani, K., Kawata, T., Katunuma, N. FEBS Lett. (1995) [Pubmed]
  2. Insights into the roles of cathepsins in antigen processing and presentation revealed by specific inhibitors. Katunuma, N., Matsunaga, Y., Himeno, K., Hayashi, Y. Biol. Chem. (2003) [Pubmed]
  3. Cathepsins B, L and D in inflammatory bowel disease macrophages and potential therapeutic effects of cathepsin inhibition in vivo. Menzel, K., Hausmann, M., Obermeier, F., Schreiter, K., Dunger, N., Bataille, F., Falk, W., Scholmerich, J., Herfarth, H., Rogler, G. Clin. Exp. Immunol. (2006) [Pubmed]
  4. Identification of cathepsin B as a mediator of neuronal death induced by Abeta-activated microglial cells using a functional genomics approach. Gan, L., Ye, S., Chu, A., Anton, K., Yi, S., Vincent, V.A., von Schack, D., Chin, D., Murray, J., Lohr, S., Patthy, L., Gonzalez-Zulueta, M., Nikolich, K., Urfer, R. J. Biol. Chem. (2004) [Pubmed]
  5. Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-betaL a process initiated by the exocytosis of cathepsin B. Guo, M., Mathieu, P.A., Linebaugh, B., Sloane, B.F., Reiners, J.J. J. Biol. Chem. (2002) [Pubmed]
  6. Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications. Guicciardi, M.E., Miyoshi, H., Bronk, S.F., Gores, G.J. Am. J. Pathol. (2001) [Pubmed]
  7. Participation of cathepsin L on bone resorption. Kakegawa, H., Nikawa, T., Tagami, K., Kamioka, H., Sumitani, K., Kawata, T., Drobnic-Kosorok, M., Lenarcic, B., Turk, V., Katunuma, N. FEBS Lett. (1993) [Pubmed]
  8. The selective role of cathepsins B and D in the lysosomal degradation of endogenous and exogenous proteins. Kominami, E., Ueno, T., Muno, D., Katunuma, N. FEBS Lett. (1991) [Pubmed]
  9. Novel physiological functions of cathepsins B and L on antigen processing and osteoclastic bone resorption. Katunuma, N., Matsunaga, Y., Matsui, A., Kakegawa, H., Endo, K., Inubushi, T., Saibara, T., Ohba, Y., Kakiuchi, T. Adv. Enzyme Regul. (1998) [Pubmed]
  10. Specific assay method for the activities of cathepsin L-type cysteine proteinases. Inubushi, T., Kakegawa, H., Kishino, Y., Katunuma, N. J. Biochem. (1994) [Pubmed]
  11. Assessment of cathepsin L activity by use of the inhibitor CA-074 compared to cathepsin B activity in human lung tumor tissue. Werle, B., Ebert, W., Klein, W., Spiess, E. Biol. Chem. Hoppe-Seyler (1995) [Pubmed]
  12. CA-074, but not its methyl ester CA-074Me, is a selective inhibitor of cathepsin B within living cells. Montaser, M., Lalmanach, G., Mach, L. Biol. Chem. (2002) [Pubmed]
  13. Participation of a cathepsin L-type protease in the activation of caspase-3. Ishisaka, R., Utsumi, T., Kanno, T., Arita, K., Katunuma, N., Akiyama, J., Utsumi, K. Cell Struct. Funct. (1999) [Pubmed]
  14. Modulation of invasive properties of murine squamous carcinoma cells by heterologous expression of cathepsin B and cystatin C. Coulibaly, S., Schwihla, H., Abrahamson, M., Albini, A., Cerni, C., Clark, J.L., Ng, K.M., Katunuma, N., Schlappack, O., Glössl, J., Mach, L. Int. J. Cancer (1999) [Pubmed]
  15. Inhibitory effect of cathepsin B inhibitor CA 074 on mouse anti-rat mixed lymphocyte reaction: novel immunosuppressive strategy for indirect xenoantigen recognition. Tohyama, T., Kiyochi, H., Narumoto, K., Honda, K., Kobayashi, N., Kanoh, M., Saibara, T., Katunuma, N. Transplant. Proc. (2000) [Pubmed]
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