Breaking the Back of BCR-ABL

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Science  03 Oct 2008:
Vol. 322, Issue 5898, pp. 17
DOI: 10.1126/science.322.5898.17a

One of the advances in the war on cancer has been the development of small molecules that target protein tyrosine kinases; one such drug, imatinib, is used to inhibit the BCR-ABL kinase in the treatment of chronic myelogenous leukemia. Nevertheless, elation has been tempered by the realization that resistance to imatinib can arise via mutation of a gatekeeper amino acid (threonine 315) to the bulkier and more hydrophobic isoleucine, which hinders access of the drug to its binding site. Similar resistance-mediating mutations have been observed for other drug-tyrosine kinase pairs in solid tumors. Not only do the mutations block drug binding, but they also tilt the kinase structure toward constitutively active conformations. Azam et al. have analyzed a series of mutations in a series of tyrosine kinases and find that the critical threonine sits atop a spine of hydrophobic residues linked to the activation loop. Replacing the threonine with isoleucine stabilizes and stiffens the spine and also enhances the coordination of ATP, thereby stimulating kinase activity. They used this insight to refine the inhibitor PD166326 into a candidate drug called compound 14, which packs neatly against the disrupted spine and inhibits the BCR-ABL variant T315I at 0.6 μM versus the lack of effect of PD166326 at 10 μM. — GJC

Nat. Struct. Mol. Biol. 15, 10.1038/nsmb.1486 (2008).

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