Leukemia response to dasatinib evaluated

08-14-2006

Scientists evaluated the response of leukemia to dasatinib (BMS-354825).

"Chronic myeloid leukemia (CML) is caused by the constitutively activated tyrosine kinase breakpoint cluster (BCR)-ABL. Current frontline therapy for CML is imatinib, an inhibitor of BCR-ABL," researchers in the United States reported.

"Although imatinib has a high rate of clinical success in early phase CML, treatment resistance is problematic, particularly in later stages of the disease, and is frequently mediated by mutations in BCR-ABL," explained J.S. Tokarski and colleagues, Bristol Myers Squibb. "Dasatinib is a multitargeted tyrosine kinase inhibitor that targets oncogenic pathways and is a more potent inhibitor than imatinib against wild-type BCR-ABL.

"It has also shown preclinical activity against all but one of the imatinib-resistant BCR-ABL mutants tested to date. Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of dasatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL."

The researchers concluded, "The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants."

Tokarski and colleagues published their study in Cancer Research (The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res, 2006;66(11):5790-5797).

For additional information, contact J.S. Tokarski, Bristol Myers Squibb, Pharmaceutical Research Institute, Dept. of Structural Biology & Modeling, POB 4000, Princeton, NJ 08543, USA.

Publisher contact information for the journal Cancer Research is: American Association Cancer Research, 615 Chestnut St., 17th Floor, Philadelphia, PA 19106-4404, USA.

Keywords: Princeton, New Jersey, United States, Chronic Myeloid Leukemia, Inhibitory Activity, Oncology, Proteins, Proteomics, Cancer Therapy, Dasatinib, BMS-354825, Tyrosine Kinase.

This article was prepared by Biotech Business Week editors from staff and other reports. Copyright 2006, Biotech Business Week via NewsRx.com.