ues were given BMS-354825 in doses ranging from 15 to 180 mg per day taken orally for five to seven days a week for a period of up to nine months. Dosing was fine-tuned for each patient based on detailed studies that examined how well the drug inhibited its target a technique that was devised by Sawyers's group for use in earlier studies in mice. Another novel facet of the study, Sawyers said, is that each patient's resistance-enhancing mutation was sequenced by Bristol-Myers Squibb scientists. This provided a wealth of information about the type of mutation carried by each patient, and allowed the researchers to correlate how the drug responded to each type of mutation.

"The identification of this compound as a drug candidate is a direct byproduct of understanding why patients develop resistance to Gleevec," said Sawyers. He notes that just as Gleevec was developed as a "molecularly targeted" inhibitor, the next generations of Gleevec, of which BMS-354825 is is one, are being refined and improved by structural biology studies that show how the drugs "fit" with their target, and how mutations alter the shape of that target.

In this case, the drug's target is the Abelson tyrosine kinase (ABL), an enzyme that becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active. The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML.

In studies published earlier this year in the journal Science, Sawyers and his colleagues demonstrated that BMS-354825 prolongs survival of mice with CML. In tests with cultured human bone marrow cells, the researchers showed that the drug inhibits the proliferation of bone marrow progenitor cells that are positive for BCR-ABL in patients who are resistant to Gleevec. "The bottom line is that our
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
5-Dec-2004

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