PNP inhibitors

Summary

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 K_i 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 K_i 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.