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imatinib ( also known as sti571 or gleevec ) is one of the great success stories of cancer therapy and is a milestone in small - molecule drug discovery and molecular targeted therapies .
imatinib is the current first - line therapy for all stages of chronic myelogenous leukemia ( cml ) , in which the chronic phase of the disease is characterized by the increased proliferation of the myeloid lineage and which is cytogenetically diagnosed by the presence of the philadelphia chromosome .
this contains a fusion gene encoding the oncoprotein bcr - abl , in which a part of the bcr protein is fused to the non - receptor abl tyrosine kinase , causing it to become constitutively active .
the deregulated kinase activity of bcr - abl accounts for the oncogenicity of the protein and is inhibited by imatinib . since the approval of imatinib by the us food and drug administration in may 2001 , there has been a dramatic reduction in the number of bone marrow transplants for cml in the us ; imatinib monotherapy has also been used successfully to induce a complete cytogenetic response in about 7590% of newly diagnosed cml patients , although drug resistance is a problem with advanced stages of cml .
imatinib is not entirely specific and targets tyrosine kinases other than abl , notably the receptor tyrosine kinases kit and pdgfr ( platelet - derived growth factor receptor ) .
this lack of specificity has been exploited in the clinic , and imatinib has also been approved for the treatment of chronic eosinophilic leukemia ( cel ) , which is caused by a fip1l1-pdgfr fusion , and for gastrointestinal stromal tumors ( gists ) , caused by mutations of kit or pdgfr ( reviewed in ) .
there has been increasing interest in understanding other potential targets of imatinib to evaluate the specificity , safety and potential off - target effects of this first - in - class drug . the traditional approach to identifying imatinib targets
is through in vitro assays with a panel of recombinant kinases to measure inhibitor binding .
this approach is limited by the pre - selection of test targets and tends to provide poor indicators for drug activity in vivo .
two recent studies circumvent this problem by using cell extracts from the cml cell line k562 to identify binding targets of imatinib . in the first
, imatinib was modified to allow attachment to solid support and incubated with cell lysates , and the bound proteins were identified by tandem mass spectrometry .
these mixed kinase inhibitor beads ( kinobeads ) were incubated with cell lysates and bound proteins were again identified by tandem mass spectrometry . to identify imatinib targets , cell lysates were pre - incubated with imatinib before binding to the kinobeads .
proteins that no longer bound to the kinobeads , because their binding sites were occupied by imatinib , were identified by comparative analysis .
both approaches have confirmed the selective nature of imatinib : no more than five proteins from k562 cell lysates bound imatinib as compared with about 30 proteins for another bcr - abl inhibitor , dasatinib .
the explanation for this difference is that dasatinib targets the active kinase conformation , which is highly conserved and thus shared by other kinases , whereas imatinib targets the inactive conformation , which is unique to the abl kinase .
surprisingly , both approaches also identified the first non - tyrosine kinase target of imatinib , nqo2 .
others may follow : indeed , a recent screen in yeast identified the vacuolar atpase ( v - atpase ) , an evolutionarily conserved proton pump , as a target of imatinib , and imatinib may interact with other non - kinase targets that could have eluded detection by the k562 cell - based experiments .
structural studies , including one just published by kuriyan and colleagues in bmc structural biology , show that this promiscuity reflects the flexibility of the inhibitor , a consideration that is likely to apply broadly to small - molecule inhibitors .
the kuriyan group has analyzed the crystal structure at 1.75  of a dimer of human nqo2 bound to imatinib .
the objective of the structural study was to cast light on possible side - effects attributable to imatinib binding to nqo2 , and a spectrophotometric assay confirmed binding of imatinib to nqo2 with a concentration for 50% inhibition ( ic50 ) of 82 nm , consistent with earlier reports   and well within the physiological range of the concentration of imatinib found in the serum of patients ( about 1 m ; referenced in ) .
nqo2 is a cytoplasmic flavoprotein that is involved in the cellular response to oxidative stress , although its mechanism of action is not well understood .
nqo2 is highly expressed in myeloid cells , and knockdown by rna interference in k562 cells results in reduced proliferation ( referenced in ) .
however , nqo2 knockout mice show myeloid hyperplasia and increased sensitivity to chemical carcinogenesis ( referenced in ) .
the potential clinical side - effect(s ) of inhibition of nqo2 , despite the elucidation of the exact mechanism of imatinib inhibition , are thus not yet clear .
the structure does show , however , that the structural flexibility that allows imatinib to bind to nqo2 is also the basis for its binding to other , more clinically relevant targets .
imatinib interacts with nqo2 primarily through hydrophobic interactions , making no direct hydrogen bonds ( figure 1a ) .
steric constraints lead imatinib to adopt a compacted horseshoe shape that partially extends into the solvent , and the isoalloxazine ring of the nqo2 flavin cofactor in the active site stacks with the pyridine and pyrimidine rings of imatinib
. the related kinase inhibitor dasatinib can not make this stacking interaction , and this explains why it does not bind to nqo2 .
the structure also demonstrates why imatinib can not bind the closely related nqo1 , which has 49% identity and a similar structure to nqo2 : steric hindrance from phe232 , tyr128 and pro68 are likely to occlude the imatinib binding site . 

atomic interactions of imatinib with ( a ) nqo2 ( protein data bank ( pdb ) code 
 1fw3 ) and ( b ) abl kinase domain ( pdb 
 1iep ) .
( a ) a monomer of nqo2 ( green ) is shown bound to its cofactor fad ( blue ) and to imatinib ( red ) .
imatinib uses stacking interactions with fad and makes hydrophobic contacts with both subunits in the nqo2 dimer .
( b ) the abl kinase domain ( cyan ) is depicted with the dfg motif ( yellow ) and residues involved in direct hydrogen binding ( blue ) either through side chains or the peptide backbone .
comparison of the nqo2-imatinib structure with that of imatinib bound to abl ( figure 1a , b ) reveals the flexibility of imatinib binding and demonstrates the difficulty in designing a drug that has no off - targets . in the abl - imatinib complexes ( reviewed in ) , the dfg motif ( asp381-phe382-gly383 ) that characterizes the activation loop of the kinase
is rotated by 180 and adopts a flipped - out conformation ( figure 1b ) .
this dfg - out conformation creates a binding pocket for imatinib , which on binding causes the activation loop to fold towards the active site and at the same time induces contraction of the phosphate - binding p - loop , which also binds to imatinib .
overall , imatinib uses six hydrogen bonds and several van der waals interactions to stabilize the complex . in the imatinib - abl complex
, imatinib adopts an extended conformation that is seen in several other kinase - imatinib structures   and that differs significantly from the compact , ring - stacking conformation seen in the nqo2 structure .
the structures of imatinib bound to the syk kinase , or to the desmethyl imatinib analog bound to src kinase , however , are similar to the conformation seen in nqo2 , which shows that this is a minor but not a unique conformation for imatinib .
future drug designs will need to account for the distinct conformations that a small molecule inhibitor can adopt if they are to understand the full range of targets that a drug can bind .
as mentioned earlier , imatinib has been approved for the treatment of cml , cel and gist because of its inhibition of the bcr - abl , pdgfr and kit tyrosine kinases ( figure 2 ) .
recent clinical and preclinical studies have expanded the use of imatinib for the treatment of other diseases , including systemic mastocytosis , which also involves the kit and pdgfr tyrosine kinases , and ( in preliminary studies ) fibrotic disorders ( reviewed in ) .
it probably acts in fibrotic disorders through effects on the abl tyrosine kinase , which has been implicated in tgf-induced fibrotic responses , and through the pdgfr : both of these are known to be involved in two major pro - fibrotic pathways activated in systemic sclerosis . 

the structure of imatinib ( from pdb 1iep ) is shown in the middle , with carbon ( green ) , nitrogen ( blue ) and oxygen ( red ) atoms displayed .
cel , chronic eosinophilic leukemia ; cml , chronic myelogenous leukemia ; gist , gastrointestinal stromal tumors ; kit , receptor for stem cell factor ; pdgfr , platelet - derived growth factor receptor ; smc , systemic mastocytosis ; ssc , systemic sclerosis ; v - atpase , vacuolar atpase . in mouse models
, there is evidence that imatinib may be effective in the treatment of ischemic strokes   and in several inflammatory and autoimmune diseases .
the effects on inflammatory and autoimmune disease are consistent with phase i clinical studies and case reports detailing positive effects in rheumatoid arthritis , psoriasis , spondyloarthritis and crohn 's disease ( referenced in ) .
a recent paper , again on a mouse model , reports that imatinib may be effective for the treatment of type 1 diabetes , largely through inhibition of pdgfr .
given the involvement of nqo2 in oxidative stress , it will be of interest to determine whether the inhibition of this oxidoreductase can contribute to the anti - inflammatory activity of imatinib
. known mild adverse effects of imatinib include edema , muscle cramps , diarrhea and bone - marrow toxicity , and these do cause some patients to discontinue treatment .
cardiotoxicity has been reported as a potentially severe adverse effect of imatinib ( reviewed in ): in this case the adverse effect seems to be due to inhibition of the primary target of imatinib , the abl kinase , but the extent to which the cardiotoxicity results from imatinib treatment is controversial .
imatinib has been shown to be a versatile drug with clinical benefit for treating cml , gist and cel and has potential for use in a variety of other diseases .
understanding how imatinib and other small - molecule drugs interact with their cellular targets is important for rational drug design and prediction of potential off - target effects .
the limited promiscuity of imatinib may be optimal , allowing its use in a variety of diseases with mild adverse effects .
imatinib has revolutionized the treatment of cml and may be poised for more clinical successes .
the protein kinase inhibitor imatinib , also known as gleevec , has been a notable success in treating chronic myelogenous leukemia . a recent paper in bmc structural biology reports a 1.75  crystal structure of imatinib bound to the oxidoreductase nqo2 and reveals insights into the binding specificity and the off - target effects of the inhibitor .