DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
tyrosine kinases under physiological conditions. In a
growing number of human malignancies, mutations that
constitutively activate protein tyrosine kinases are
implicated in malignant transformation; thus, protein
tyrosine kinases are targets for cancer therapy.
Inhibitors of the BCR-ABL Kinase:
Imatinib, Dasatinib, and Nilotinib
Imatinib mesylate (STI 571, GLEEVEC, GLIVEC) was the
first molecularly targeted protein kinase inhibitor to
receive FDA approval. It targets the BCR-ABL tyrosine
kinase, which underlies chronic myelogenous
leukemia (CML). A single molecular event, in this case
the 9:22 translocation, leads to expression of the
Abelson proto-oncogene kinase ABL fused to BCR
(breakpoint cluster region), yielding a constitutively
activated protein kinase, BCR-ABL, and then the
malignant phenotype. Imatinib and the related compounds
dasatinib and nilotinib induce clinical and
molecular remissions in >90% of CML patients in the
chronic phase of disease. Imatinib effectively treats
other tumors that carry related tyrosine kinase mutations,
including GI stromal tumors (driven by c-KIT
mutation) (Blanke et al., 2008), and hypereosinophilia
syndrome, chronic myelomonocytic leukemia, and dermatofibrosarcoma
protuberans (all driven by mutations
that activate the platelet-derived growth factor receptor,
PDGFR) (Sirvent et al., 2003).
Chemistry. Imatinib was identified through high-throughput screening
against the BCR-ABL kinase. The lead compound of this series,
a 2-phenylaminopyrimidine, had low potency and poor specificity,
inhibiting both serine/threonine and tyrosine kinases (Buchdunger
et al., 2001). The addition of a 3′-pyridyl group at the 3′ position of
the pyrimidine enhanced its potency. Further modifications resulted
in improved activity against PDGFR and c-KIT and loss of serine/
threonine kinase inhibition. Introduction of N-methylpiperazine as a
polar side chain greatly improved water solubility and oral bioavailability,
yielding imatinib, an inhibitor of the closed, or inactive, configuration
of the kinase:
N
N
N
H
N
CH 3
N
CH 3
HN
Dasatinib (BMS-354825, SPRYCEL), a second-generation
BCR-ABL inhibitor, was developed using a series of substituted
2-(aminopyridyl) and 2-(aminopyrimidinyl) thiazol-5-carboxyamides.
O
N
It inhibits the Src kinase, and unlike imatinib, it binds both the open
and closed configurations of the BCR-ABL kinase (Shah et al., 2004).
HO
Nilotinib (AMN107, TASIGNA) was designed to have
increased potency and specificity compared to imatinib. Its structure,
based on crystallographic studies of the BCR-ABL kinase, promotes
hydrogen bonding to Glu286 and Asp381 (Weisberg et al.,
2005) and overcomes mutations that cause imatinib resistance.
N
N
N
H
N
N
H 3 C
N
N
O
N
CH 3
H 3 C
N
H
Mechanism of Action. Crystallographic and mutagenesis studies
indicate that imatinib and nilotinib bind to a segment of the kinase
domain that fixes the enzyme in a closed or nonfunctional state, in
which the protein is unable to bind its substrate/phosphate donor,
ATP (Weisberg et al., 2005). The three BCR-ABL kinase inhibitors
differ in their potency of inhibition, their binding specificities, and
their susceptibility to resistance mutations in the target enzyme.
Dasatinib [(IC 50
) = <1 nM] and nilotinib [(IC 50
) = <20 nM] (Weisberg,
2005) inhibit BCR-ABL kinase more potently than does imatinib
[(IC 50
) = 100 nM].
Mechanisms of Resistance. Resistance to the tyrosine kinase
inhibitors arises from point mutations in three separate segments of
the kinase domain (Figure 62–1). The contact points between imatinib
and the enzyme become sites of mutations in drug-resistant
leukemic cells; these mutations prevent tight binding of the drug and
lock the enzyme in its open configuration, in which it has access to
substrate. Most such mutations hold the enzyme in its open and
enzymatically active confirmation. The most common resistance
mutations affect amino acids 255 and 315, both of which serve as
contact points for imatinib; these mutations confer high-level resistance
to imatinib and nilotinib. Dasatinib is unaffected by mutation at
255 but is ineffective in the presence of mutation at 315. Nilotinib
retains inhibitory activity in the presence of most point mutations
(except at 315) that confer resistance to imatinib (Weisberg et al.,
2005; O’Hare et al., 2005).
Other mutations affect the phosphate-binding region and the
“activation loop” of the domain with varying degrees of associated
resistance. Some mutations, such as at amino acids 351 and 355,
do not affect response to dasatinib or nilotinib but confer low levels
of resistance to imatinib (O’Hare et al., 2005; Corbin et al., 2003).
H
N
N
N
S
N
CF 3
OCl
N
H
H 3 C