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PNP complex were used, mainly because of the magnitude of the changes that occur during substrate
binding. We found that computer modeling required significant tuning in order to provide useful results.
Crystallographic results were useful in testing and modifying modeling parameters. The most useful
modeling results were achieved after incorporation of the conformational searching techniques described
earlier and when the coordinates for the PNP-guanine complex model were used. Visual inspection and
chemical intuition were very important.
B. Perspectives of Treating Targeted Disease
One of the inhibitors designed during the drug discovery process, 9-(3-pyridylmethy)-9-deazaguanine
(BCX-34), was selected for initial clinical development. Current clinical trials utilize both topical and
oral formulations of the drug.
Researchers at the University of Alabama at Birmingham and Washington University School of
Medicine have recently completed small Phase II clinical trials of two indicated applications, cutaneous
T-cell lymphoma (CTCL) and psoriasis, using a topical formulation of BCX-34. Although patients
showed improvement in both trials, the duration of each was too short (six weeks) to adequately assess
the efficacy of the drug. Subsequently 80% of the patients from the CTCL trial (24 patients) entered an
open label trial for treatment of their disease for up to twelve months. At the end of the first six months
of treatment, seven of the patients were in complete remission (verified by biopsy), two patients showed
a clinical complete response, and nine patients had shown definite improvement. The other six patients
had shown no change or progression of disease. No serious, drug-related adverse events were reported
during the study.
The process of structure-based drug design helped to ensure that the inhibitor would be highly selective
for the PNP enzyme, and thus far no other targets for the drug have been identified. The mechanism of
action of BCX-34 appears to be entirely related to its effect on the proliferation of human T-cells. This
high degree of specificity probably also contributes to the high safety profile of the drug. Although longterm
studies in more patients will be necessary to substantiate these results, it appears likely that BCX-
34 will have a significant clinical effect on at least some T-cell mediated diseases.
Based on the results from these three trials, BioCryst has initiated a multicenter Phase III trial for the
treatment of CTCL, as well as a large, multicenter Phase II trial for psoriasis. In addition to the two
clinical trials using the topical formulation, a Phase I clinical trial in CTCL and T-cell
lymphoma/leukemia has begun using an oral formulation of BCX-34. In the future, a number of other Tcell
mediated diseases or processes are possible targets for BCX-34, including rheumatoid arthritis,
multiple sclerosis, inflammatory bowel disease, and organ transplant rejection.
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