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New Tyrosine Kinase Inhibitor More Potent Than STI-571 in CML Cell Lines

New Tyrosine Kinase Inhibitor More Potent Than STI-571 in CML Cell Lines

Bcr-Abl tyrosine kinase inhibitor PD173955 (PD17) binds to the target ATP
binding pocket even more efficiently than STI-571 (imatinib mesylate, Gleevec).
It shows 15 to 20 times greater efficacy in chronic myelogenous leukemia (CML)
cell lines because it can bind to either open or closed activation loops.

Bayard D. Clarkson, MD, presented the research at the
Molecular Targets and Cancer Therapeutics meeting, sponsored by the American
Association for Cancer Research, National Cancer Institute, and European
Organization for Research and Treatment of Cancer (abstract 568).

"We basically pulled this compound out of the
literature, synthesized it, and found that it worked," said Dr. Clarkson,
Enid A. Haupt Chair of Therapeutic Research and head of the Hematopoietic Cell
Kinetics Laboratory at Memorial Sloan-Kettering Cancer Center. The MSKCC
researchers collaborated with Dr. John Kuriyan and other Rockefeller University
investigators on the x-ray crystal structure work.

The initial translocation between chromosomes 9 and 22 in
CML produces a BCR-encoded sequence fused to a truncated c-Abl gene. The
Bcr-Abl protein encoded by this mutation greatly in-creases c-Abl’s tyrosine
kinase activity and causes the clinical manifestations of CML. STI-517 produces
complete hematologic responses in most cases of CML because it binds to an ATP
binding pocket and blocks this process.

Dr. Clarkson’s team set out to find inhibitors of Bcr-Abl
that might be more effective than STI-571, which is met by resistance in
patients whose CML is in blastic phase.

PD17 is more effective than STI-571 at inhibiting cell lines
containing Bcr-Abl in vivo and at blocking CML progenitor cells without
inhibiting normal progenitor cells. In vitro assays showed that PD17 inhibited
fresh CML primary progenitor cells in the low nanomolar range. Dr. Clarkson
said that PD17 is active and tolerable in mice at levels that should be active
in humans.

He presented x-ray crystal structures of the catalytic
domain of c-Abl (Abl kinase) complexed with either STI-571 or PD17. These
showed that STI-571 can bind to the target site only when the 21-residue
activation loop of c-Abl is in a closed configuration that resembles substrate
binding. PD17 binds when the activation loop is open and resembles that of an
active kinase.


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