A new class of compds. C6-unsubstituted [3,4d]pyrimidines with a remarkable inhibitory activity on either ABL and SRC kinases has recently been synthesized. Two of them proved to have cytotoxic effects on Ba/F3 cell line transducing with the wild type BCR-ABL or three of the most common BCR-ABL mutations assocd. with imatinib mesylate (IM) resistance in vivo. The present study demonstrates two C6-unsubstituted pyrazolo[3,4d] pyrimidines that are very effective against early (CD34+ ) chronic myeloid leukemia progenitors sensitive to IM or driven towards IM resistance by the BCR-ABL mutation T315I and other mutations while exhibiting a low inhibitory activity on the normal counterpart.
New SRC/ABL inhibitors for chronic myeloid leukemia therapy show selectivity for T315I ABL mutant CD34(+) cells.
SCHENONE, SILVIA
2010-01-01
Abstract
A new class of compds. C6-unsubstituted [3,4d]pyrimidines with a remarkable inhibitory activity on either ABL and SRC kinases has recently been synthesized. Two of them proved to have cytotoxic effects on Ba/F3 cell line transducing with the wild type BCR-ABL or three of the most common BCR-ABL mutations assocd. with imatinib mesylate (IM) resistance in vivo. The present study demonstrates two C6-unsubstituted pyrazolo[3,4d] pyrimidines that are very effective against early (CD34+ ) chronic myeloid leukemia progenitors sensitive to IM or driven towards IM resistance by the BCR-ABL mutation T315I and other mutations while exhibiting a low inhibitory activity on the normal counterpart.
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