Blood, 15 January 2007, Vol. 109, No. 2,
part of an article in Blood Online
CLINICAL TRIALS AND OBSERVATIONS
MK-0457: a light at the end of the tunnel?
Martinelli, G. Baccarani, M.
Comment on Giles et al, page 500
"MK-0457: a light at the end of the tunnel?
Giovanni Martinelli, Simona Soverini, Ilaria Iacobucci, and Michele Baccarani
UNIVERITY OF BOLOGNA
In this issue of Blood, Giles and colleagues report the remarkable clinical activity of MK-0457, an aurora kinase inhibitor, in 3 Philadelphia chromosome–positive leukemia patients harboring the highly resistant T315I mutation.
To counteract the problem of imatinib resistance due to BCR-ABL gene mutations in Philadelphia chromosome–positive (Ph+) leukemias, several new drugs have been tested in preclinical assays, and 3 of them are currently in clinical development: the dual-specificity Src/Abl inhibitors dasatinib (BMS354825) and SKI606, and the imatinib derivative nilotinib (AMN-107). Nevertheless, the T315I mutant has remained an Achilles heel for at least 2 of these second-generation inhibitors (ie, nilotinib and dasatinib).1,2 Structural analyses predict that the T315I eliminates a crucial hydrogen bond required for high-affinity binding of imatinib, dasatinib, and nilotinib, and alters adversely the topology of the ATP-binding pocket.3
In this issue of Blood, Giles and colleagues document for the first time the efficacy of a tyrosine kinase inhibitor in T315I-positive patients—2 patients with chronic myeloid leukemia (CML) in accelerated phase and a patient with Ph+ acute lymphoblastic leukemia (ALL), resistant both to imatinib and to dasatinib or nilotinib, who received MK-0457 within a phase 1/2 study. All 3 patients achieved clinical responses to doses that were not associated with adverse events.
The use of this aurora kinase inhibitor in the treatment of Ph+ leukemias found its rationale in the results of a recent screening4 of existing chemical compounds for their ability to bind and inhibit drug-resistant mutant variants of Bcr-Abl, including the T315I. The study revealed that MK-0457 binds T315I Bcr-Abl with very high affinity (Kd = 5 nM). Subsequent cocrystal studies showed that MK-0457 binds Bcr-Abl in a mode that accommodates the substitution of the bulkier isoleucine for threonine at residue 315 (see figure), and for this reason effectively inhibits the kinase activity of both wild-type and T315I Bcr-Abl in vitro at micromolar concentrations.5 Despite the small number of T315I-positive patients treated with MK-0457 and the very short follow-up, the clinical observations of Giles and colleagues seem to fully validate this preclinical evidence."
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