PNP inhibitors


Purine nucleoside phosphorylase catalyzes the reversible phosphorolysis of purine ribonucleosides and 2′-deoxyribonucleosides to the free base and ribose-1-phosphate or 2′-deoxyribose-1-phosphate. PNP isolated from humans is specific for guanosine, inosine and certain analogs, although PNPs from other organisms show varying levels of specificity. Interest in PNP arises from its critical role in purine nucleoside metabolism and in T-cell function, which indicates that inhibitors of this enzyme might be useful in the treatment of T-cell proliferative diseases such as T-cell leukemias and lymphomas, in the suppression of host versus graft response in organ transplant patients, and in the treatment of T-cell-mediated autoimmune diseases. Most potent inhibitors of this enzyme are derivatives of guanine or 8-aminoguanine, including 9-arylmethyl derivatives. Of these, 9-benzylguanines substituted at position 2 or 3 of the phenyl ring by a side chain terminating in a phosphonate moiety are the most potent, with Ki in the nanomolar range. However, these compounds have limited potential as drugs because of their very low cell permeability. As a result, inhibitors of this type that have been tested are effective in whole cells only at concentrations of 100 µM or higher. On the other hand, the three-dimensional structure of human PNP, determined by X-ray crystallography, has been used in designing novel inhibitors of this key enzyme, resulting in several families of membrane-permeable inhibitors with IC50 values in the 6—30 nM range. The inhibition is competitive with respect to both inosine and phosphate. 9-(3-Pyridylmethyl)-9-deazaguanine (BCX-34) was chosen from these inhibitors for further study. Its Ki for the inhibition of human erythrocytic PNP is 31 nM, and its IC50 for inhibition of the proliferation of T cells (CCRF-CEM) is 1.4 µM in the presence of 5.6 µM of 2′-deoxyguanosine, which alone has no effect on cells. It did not inhibit the proliferation of B cells (MGL-8) up to 30 µM. Phase I/II clinical studies of a dermal formulation of BCX-34 have shown this drug to be efficacious and safe in the treatment of cutaneous T-cell lymphoma and psoriasis.

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  1. 1

    Parks Jr., R.E., Stoeckler, J.D., Cambor, D., Savarese, T.M., Crabtree, G.W. and Chu, S.-H., In Sartorelli, A., Lazo, J.S. and Bertino, J.R. (Eds.) Molecular Actions and Targets for Cancer Chemotherapeutic Agents, Academic Press, New York, NY, 1981, pp. 229–252.

    Google Scholar 

  2. 2

    Stoeckler, J.D., In Glazer, R.I. (Ed.) Developments in Cancer Chemotherapy, CRC Press, Boca Raton, FL, 1984, pp. 35–60.

    Google Scholar 

  3. 3

    Ealick, S.E., Rule, S.A., Carter, D.C., Greenhough, T.J., Babu, Y.S., Cook, W.J., Habash, J., Helliwell, J.R., Stoeckler, J.D., Parks Jr., R.E., Chen, S.-F. and Bugg, C.E., J. Biol. Chem., 265 (1990) 1812.

    Google Scholar 

  4. 4

    Ealick, S.E., Babu, Y.S., Bugg, C.E., Erion, M.D., Guida, W.C., Montgomery, J.A. and Secrist III, J.A., Proc. Natl. Acad. Sci. USA, 88 (1991) 11540.

    Google Scholar 

  5. 5

    Zimmerman, T.P., Gersten, N.B., Ross, A.F. and Miech, R.P., Can. J. Biochem., 49 (1971) 1050.

    Google Scholar 

  6. 6

    Cory, J.G. and Cory, A.H. (Eds.) Inhibitors of Ribonucleoside Diphosphate Reductase Activity, Pergamon Press, New York, NY, 1989.

    Google Scholar 

  7. 7

    Markert, M.L., Immunodefic. Rev., 3 (1991) 45.

    Google Scholar 

  8. 8

    Otterness, I.G. and Bliven, M.L., In Rainsford, K.D. and Velo, G.P. (Eds.) New Developments in Antirheumatic Therapy, Kluwer Academic, Norwell, MA, 1989, pp. 277–304.

    Google Scholar 

  9. 9

    Montgomery, J.A., Med. Res. Rev., 13 (1993) 209.

    Google Scholar 

  10. 10

    Williams, S.R., Goddard, J.M. and Martin Jr., D.W., Nucleic Acids Res., 12 (1984) 5779.

    Google Scholar 

  11. 11

    Montgomery, J.A., Niwas, S., Rose, J.D., Secrist III, J.A., Babu, Y.S., Bugg, C.E., Erion, M.D., Guida, W.C. and Ealick, S.E., J. Med. Chem., 36 (1993) 55.

    Google Scholar 

  12. 12

    Secrist III, J.A., Niwas, S., Rose, J.D., Babu, Y.S., Bugg, C.E., Erion, M.D., Guida, W.C., Ealick, S.E. and Montgomery, J.A., J. Med. Chem., 36 (1993) 1847.

    Google Scholar 

  13. 13

    Erion, M.D., Niwas, S., Rose, J.D., Ananthan, S., Allen, M., Secrist III, J.A., Babu, Y.S., Bugg, C.E., Guida, W.C., Ealick, S.E. and Montgomery, J.A., J. Med. Chem., 36 (1993) 3771.

    Google Scholar 

  14. 14

    Stoeckler, J.D., Ryden, J.B., Parks Jr., R.E., Chu, M.-Y., Lim, M.-I., Ren, W.-Y. and Klein, R.S., Cancer Res., 46 (1986) 1774.

    Google Scholar 

  15. 15

    Kazmers, I.S., Mitchell, B.S., Daddona, P.E., Wotring, L.L., Townsend, L.B. and Kelley, W.N., Science, 214 (1981) 1137.

    Google Scholar 

  16. 16

    Osborne, W.R.A. and Barton, R.W., Immunology, 59 (1986) 63.

    Google Scholar 

  17. 17

    Slichter, S.J., Deeg, H.J. and Osborne, R.A., Br. J. Haematol., 75 (1990) 591.

    Google Scholar 

  18. 18

    Benear, J.B., Frederick, D., Townsend, L. and Epstein, R.B., Transplantation, 41 (1986) 274.

    Google Scholar 

  19. 19

    Shewach, D.S., Chern, J.-W., Pillote, K.E., Townsend, L.B. and Daddona, P.E., Cancer Res., 46 (1986) 519.

    Google Scholar 

  20. 20

    Sircar, J.C. and Gilbertsen, R.B., Drugs Future, 13 (1988) 653.

    Google Scholar 

  21. 21

    Burley, S.K. and Petsko, G.A., Science, 229 (1985) 23.

    Google Scholar 

  22. 22

    Woo, P.W.K., Kostlan, C.R., Sircar, J.C., Dong, M.K. and Gilbertsen, R.B., J. Med. Chem., 35 (1992) 1451.

    Google Scholar 

  23. 23

    Yen, C.Y., Chern, J.W. and Wang, H.H., Chin. Pharm. J., 42 (1990) 249.

    Google Scholar 

  24. 24

    Gilbertsen, R.B., Scott, M.E., Dong, M.K., Kossarek, L.M., Bennett, M.K., Schrier, D.J. and Sircar, J.C., Agents Actions, 21 (1987) 272.

    Google Scholar 

  25. 25 a.

    Gilbertsen, R.B., Dong, M.K. and Kossarek, L.M., Agents Actions, 22 (1987) 379.

    Google Scholar 

  26. 25 b.

    Gilbertsen, R.B., Josyula, U., Sircar, J.C., Dong, M.K., Wu, W., Wilburn, D.J. and Conroy, M.C., Biochem. Pharmacol., 44 (1992) 996.

    Google Scholar 

  27. 26

    Stein, J.M., Stoeckler, J.D., Li, S.-Y., Tolman, R.L., MacCoss, M., Chen, A., Karkas, J.D., Ashton, W.T. and Parks Jr., R.E., Biochem. Pharmacol., 36 (1987) 1237.

    Google Scholar 

  28. 27

    Bzowska, A., Kulikowska, E., Shugar, D., Bing-Yi, C., Lindborg, B. and Johansson, N.G., Biochem. Pharmacol., 41 (1991) 1791.

    Google Scholar 

  29. 28

    Tuttle, J.V. and Krenitsky, T.A., J. Biol. Chem., 259 (1984) 4065.

    Google Scholar 

  30. 29

    Krenitsky, T.A., Tuttle, J.V., Miller, W.H., Moorman, A.R., Orr, G.F. and Beauchamp, L., J. Biol. Chem., 265 (1990) 3066.

    Google Scholar 

  31. 30

    Nakamura, C.E., Chu, S.-H., Stoeckler, J.D. and Parks Jr., R.E., Biochem. Pharmacol., 35 (1986) 133.

    Google Scholar 

  32. 31

    Nakamura, C.E., Chu, S.-H., Stoeckler, J.D. and Parks Jr., R.E., Nucleosides Nucleotides, 8 (1989) 1039.

    Google Scholar 

  33. 32

    Babu, Y.S. and Montgomery, J.A., unpublished data.

  34. 33

    Halazy, S., Ehrhard, A. and Danzin, C., J. Am. Chem. Soc., 113 (1991) 315.

    Google Scholar 

  35. 34

    Mamont, P.S., Weibel, M., Danzin, C. and Halazy, S., Int. J. Pur. Pyr. Res., 2 (1991) 62.

    Google Scholar 

  36. 35

    Sediva, K., Ananiev, A. V., Votruba, I., Holy, A. and Rosenberg, I., Int. J. Pur. Pyr. Res., 2 (1991) 35.

    Google Scholar 

  37. 36

    Jordan, F. and Wu, A., Arch. Biochem. Biophys., 190 (1978) 699.

    Google Scholar 

  38. 37

    Salamone, S.J. and Jordan, F., Biochemistry, 21 (1982) 6383.

    Google Scholar 

  39. 38

    Dempcy, R.O. and Skibo, E.B., Biochemistry, 30 (1991) 8480.

    Google Scholar 

  40. 39

    Willis, R.C., Robins, R.K. and Seegmiller, J.E., Mol. Pharmacol., 18 (1980) 287.

    Google Scholar 

  41. 40

    Erickson, J.W. and Fesik, S.W., Annu. Rep. Med. Chem., 27 (1992) 271.

    Google Scholar 

  42. 41

    Halazy, S., Eggenspiller, A., Ehard, A. and Dancin, C., Bioorg. Med. Chem. Lett., 2 (1992) 407.

    Google Scholar 

  43. 42

    Kelly, J.L., Linn, J.A., McLean, E.W. and Tuttle, J.V., Abstract Med:104 of the 205th ACS National Meeting, Denver, CO, March 28–April 2, 1993.

  44. 43

    Montgomery, J.A., Snyder Jr., H.W., Walsh, D.A. and Walsh, G.M., Drugs Future, 18 (1993) 887.

    Google Scholar 

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Correspondence to John A. Montgomery.

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Montgomery, J.A., Secrist, J.A. PNP inhibitors. Perspectives in Drug Discovery and Design 2, 205–220 (1994).

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Key words

  • Purine nucleoside phosphorylase
  • T-cell proliferative diseases
  • Autoimmune diseases
  • Guanosine
  • 8-Aminoguanosine
  • 8-Amino-9-arylmethylguanines
  • Acyclovir diphosphate
  • 9-Arylmethyl-9-deazaguanines
  • 9-(3-Pyridylmethyl)-9-deazaguanine
  • BCX-34