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Bcr-Abl tyrosine kinase inhibitor (TKI) is the initial choice of treatment for most patients with Chronic myelogenous leukemia (CML). In more than 90% cases CML is caused by chromosomal abnormality resulting in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Janet Rowley in 1972 and is due to fusion between Abelson (Abl) tyrosine kinase gene at chromosome 9 and break point cluster (Bcr) gene at chromosome 22. This results in a constitutively active Bcr-Abl tyrosine kinase and has been implicated in the pathogenesis of CML. Compounds have been developed that selectively inhibit the Bcr-Abl tyrosine kinase that results from a chimeric Bcr-Abl oncogene. Before the FDA approval of imatinib in 2001 no drugs were used that changed the natural progression of CML, only cytotoxic drugs such as busulfan, hydroxyurea or interferon-alpha (rIFN-α). Even though the first Bcr-Abl tyrosine kinase was named “the magic bullet” to cure cancer by The Times a second generation of Bcr-Abl TKI has been developed as a cause of resistance to imatinib. The resistance in patients is mainly caused by point mutations within the Abl kinase domain, over-expression of Bcr-Abl, increased production of transmembrane plasma proteins or constitutive activating of downstream signaling molecules such as Src-family kinases. Most of the drugs are adenosine triphosphate (ATP)-competitive inhibitors.[1]

History

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CML has a well defined molecular target and relatively selective therapies aimed at that target, which is not the case for the majority of cancers and chemotherapies today.[2] Bcr-Abl was regarded as highly attractive target for drug intervention since the Bcr-Abl fusion gene encodes a constitutively activated kinase. Drug discovery that specifically targeted the ATP binding site of a single kinase was regarded as quite a challenging task since hundreds of protein kinases were known in the human genome.[3] In the presence of TKI the binding of ATP is blocked, phosphorylation is prevented and Bcr-Abl expressing cells either have a selective growth disadvantage or they undergo apoptotic cell death.[4][5]

First Generation Bcr-Abl Tyrosine Kinase Inhibitors

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Imatinib (STI571)

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Imatinib, (Gleevec) was discovered in 1992 [6] and is regarded as first generation drug since it is the first Bcr-Abl tyrosine kinase inhibitor to be used in the treatment of CML.

Development

Evolution of Pyrimidin A to imatinib

In the development of imatinib, the structure of Bcr-Abl tyrosine kinase played a limited role because it was unknown.[7] A high-throughput screening of chemical libraries at Novartis was performed to identify a starting molecule, which was called pyrimidine A. This compound served as a lead compound and was then tested and modified to develop imatinib.[8] With a replacement of the imidazole group with a benzamido group, the compounds specificity increased while its activity as a kinase inhibitor remained the same. Subsequently, introducing a methyl subtituent ortho to the pyrimidinyl-amino group enhanced the potency.[3]

Binding Since then crystallographic studies have revealed that imatinib binds to the kinase domain of Abl only when the domain adopts the inactive or "closed" conformation.[9] This is where the glycine-rich, P-binding phosphate loop (P-loop) folds over the ATP binding site and the activation-loop adopts a conformation in which it occludes the substrate binding site and disrupts the ATP phosphate binding site to block the catalytic activity of the enzyme.[10] The shift of the AspPheGly triad at the N-terminal end of the activation loop results in the exposure of a binding pocket which can be utilized by inhibitors.[11]

Imatinib binds to Abl domain via six hydrogen bond interactions. This stabilizes the imatinib Bcr-Abl complex and prevents ATP from reaching its binding site.[6][9][3] The hydrogen bonds involve the pyridine-N and backbone-NH of Met-318, the aminopyrimidine and side chain hydroxyl of Thr-315, tha amide-NH and side chain carboxylate of Glu-285, the carbonyl and backbone-NH of Asp-381, the protonated methylpiperazine with the backbone-carbonyl atoms of Ile-360 and His-361. Additionaly, a number of van der Waals interactions contribute to binding.[6] A hydrophobic pocket is formed by amino acid residues Ile-293, Leu-298, Leu-354 and Val-379 around the phenyl ring adjacent to the piperazinyl-methyl group of imatinib.[9] At the time of it's discovery, in the absence of structural information, no clear explanation for the impressive selectivity of imatinib could be found.[5]

Although first- generation treatment achieved an extremely high response rate and a low relapse rate in CML patients, some patients do experience resistance or intolerance to imatinib.[1]

Drug Resistance

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Drug resistance is the main drive in continuing research and development of Bcr-Abl TKI. Shortly after the introduction of imatinib, investigators began to describe a number of in vitro derived cell lines with resistance to the drug. This was rapidly followed by the clinical description of imatinib resistant cells in patients, which has resulted in efforts to understand better the biology behind these observations. Assessments of therapeutic response of imatinib in patients with CML are based upon meeting hematologic, cytogenic and molecular milestones. Patients that fail to achieve defined responses at predefined chronological time points are described as primarily resistant to therapy, and those losing previously obtained milestones in disease regression are termed secondarily resistant.[2] Before conclusion is drawn, it is important to consider that retrospective data has showed a high incidence of imatinib non-compliance in CML patients and this could lead to undesired clinical outcomes.[1]

Common mechanisims of resistance to TKIs

In general, imatinib resistance can be subdivided into Bcr-Abldependent and independent mechanisms. Bcr-Abl dependent mechanisms include over expression or amplification of the Bcr-Abl gene and point mutations within the Bcr-Abl kinase domain that interfere with imatinib binding. Bcr-Abl independent mechanisms include factors influencing the concentration of imatinib within the cell, for example by alterations in drug influx and efflux and activation of Bcr-Abl independent pathways, such as members of the Src kinase family [1]. Imatinib resistance can also be produced by other mechanisms that will not be mentioned here as the importance of those mechanisms still remain a question due to lack of clinical data.

Bcr-Abl Dependent Mechanisms of Resistance

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Bcr-Abl duplication

The first reports of resistance to imatinib described a development of oncogene amplification. That is, the gene that encodes for the pathogenic Bcr-Abl tyrosine kinase is duplicated in the DNA sequence, leading to higher expression of the pathogen.[2] Increasing the imatinib dose could surmount this kind of resistance, provided that severe or intolerable adverse effects are not produced.[1]

Bcr-Abl mutation

Point mutations can cause amino acid substitutions inside the kinase domain of the Bcr-Abl protein and disrupt the binding site of imatinib on the tyrosine kinase, resulting in a loss of sensitivity to the drug. These mutations normally affect the structure of the Bcr-Abl protein, leading either to interruption of critical contact points between the drug and the Bcr-Abl protein or induction of a conformational change, resulting in a protein that imatinib is unable to bind to.[1]

Mutational frequencies appear to increase as the disease, CML, progresses from chronic phase to the blast phase. The most important mutations are the P-loop mutations and the T315I mutation. Mutations on other sites of the kinase have also been reported, for example on the C-helix, SH2 domain, substrate binding site, activation loop and C-terminal lobe. Some of these mutations have clinical significance, but none as much as P-loop and T315I mutations.[2]

-T315I mutation

The T315I is a unique mutation because of its resistance to all approved Bcr-Abl inhibitors.[12] The T315I mutation is caused by a single C->T nucleotide substitution at position 944 of the Abl gene, resulting in a threonine to isoleucine substitution at amino acid 315 of the Abl protein sequence. This amino acid substitution eliminates a critical oxygen molecule needed for hydrogen bonding between imatinib and the Abl kinase, and also creates steric hindrance to the binding of most TKIs.[2] When this mutation was discovered it was estimated that every 6 out of 9 cases of advanced stage CML with imatinib resistance had this mutation.[13] This mutation produces the highest magnitude of resistance to not only imatinib but also to second generations TKIs.[1]

-P-loop mutations

The structure of Bcr-Abl contains two flexible loops, the ATP-binding P-loop and the activation loop. These loops have specific arrangements in the inactive conformation of Bcr-Abl that stabilize the basal conformation. Mutations in these loops destabilize arrangement of the loops such that the kinase domain cannot assume the inactive conformation required for imatinib binding. Mutations in the P-loop region are the most common, accounting for 36-48% of all mutations. There are clinical data indicating that Bcr-Abl mutations in the P-loop is 70-100 fold less sensitive to imatinib compared with native Bcr-Abl.[1]

Bcr-Abl Independent Mechanisms of Resistance

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Additional mechanisms have been postulated to describe resistance seen in various model systems although none have been clearly identified as a sole source of clinical resistance.[2]

Drug efflux caused by P-glycoproteins

Some investigations in cell lines have shown that imatinib resistance may be partly due to an increase in the expression of the P-glycoprotein efflux pump. By utilizing agents that inhibit P-glycoprotein activity imatinib susceptibility has been restored in some cases.[2]

Drug import by organic cation transporter 1

The entry of imatinib into cells is dependent on an organic import transporter (OCT1). OCT1 plays a significant role in imatinib resistance by inhibiting its influx and thus decreasing the intracellular bioavailability of imatinib.[14] Patients with low expression, activity or polymorphisms of OCT1 had significantly lower intracellular levels of imatinib. The response of patients with low OCT1 activity was significantly dose-dependant. This data indicates that OCT1 activity is an important determinant in the molecular response to imatinib.[1]

Alternative signaling pathway activation

In a few patient groups, resistance may be caused by the activation of other signaling pathways, particularly the Src family kinases. The Src family kinases have been implicated in Bcr-Abl signaling and mediate imatinib resistance by stabilizing the active conformation of Bcr-Abl, a conformation that does not bind imatinib. Furthermore, increasing evidence suggests that Src family kinases are also involved in Bcr-Abl-independent forms of imatinib resistance.

Solutions

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The treatment options for imatinib resistant or intolerant CML patients may include strategies such as increasing the dose of imatinib or the use of second-generation drugs. Escalation of imatinib-doses has shown to overcome some cases of primary resistance to imatinib, such as Bcr-Abl duplication, but the response is usually short acting.[1] In the case of resistance or intolerance, it could be helpful to test for Bcr-Abl mutations to direct the choice of second line treatment as the variable options have different function profile against the different mechanisms of resistance.[12] Second-generation drugs offer improved potency and a greater likelihood of success in resistant patients.[1] There is also a growing interest in testing the hypothesis that administration of multiple Abl kinase inhibitors in early phase patients could be used to delay or prevent the emergence of drug resistant clones. The combination of two agents targeting different pathways involved in CML may significantly improve response rates and potentially increase survival.[15]

Second Generation Drugs

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Due to increasing resistance and intolerance to imatinib efforts were made to develop new drugs that could inhibit the Bcr-Abl tyrosine kinase. This led to the discovery of second generation drugs. While drug screening was used to develop imatinib, second generation TKI’s were developed with rational drug design approach due to increased knowledge in structural biology of the Bcr-Abl tyrosine kinase.[7] Second generation drugs that are currently marketed are nilotinib and dasatinib and more drugs are being tested in clinical trials.

Nilotinib (AMN107)

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Development Nilotinib is a phenylamino-pyrimidine derivative that is structurally related to imatinib.[10] It was developed based on the structure of the Abl-imatinib complex to address the need associated with imatinib intolerance and resistance.[11][15][16] Small changes were made on the imatinib molecule to make it more potent and selective as a Bcr-Abl inhibitor and these changes resulted in the discovery of nilotinib. Nilotinib is a selective Bcr-Abl kinase inhibitor.[11][15]

Nilotinib is 10-30 fold more potent than imatinib in inhibiting activity of the Bcr-Abl tyrosine kinase and proliferation of Bcr-Abl expressing cells. [10][15][16][17].The drug effectively inhibits the auto phosphorylation of Bcr-Abl on Tyr-177 that is involved in CML pathogenesis.[17] Synergistic activity of imatinib and nilotinib has been reported following coadministration. This might be a result of the fact that the drugs are taken up in cells by different mechanisms whereas imatinib influx is dependent of OCT1 but nilotinib is not. Also nilotinib is not a substrate for efflux transporter P-glycoprotein pump unlike imatinib.[15][17] Although the two dimensional molecular structures of these two drugs might look similar they are neither in terms of spatial structure nor molecular properties.[11]

Binding

Nilotinib in it's binding site

Nilotinib binds to the inactive conformation of the Abl kinase domain, largely through lipophilic interactions and thus blocks its catalytic activity.[10][15] Nilotinib binds to the kinase domain by making four hydrogen bond interactions involving the pyridyl-N and the backbone NH of Met-318, the anilino-NH and the side chain OH of Thr-315, the amido-NH and side chain carboxylate of Glu-286 and the amido carbonyl with the backbone NH of the Asp-381.[11][17] The [4-(3-pyridinyl)-2-pyrimidinyl] anilino segment of nilotinib has close binding interactions with Met-318, Phe-317 and Thr-315 residues of a region within the ATP binding site. The remaining half of the compound extends beyond the Thr-315 gatekeeper residue to bind within an additional pocket. The 3-methylimidazole and trifluoro-methyl groups of nilotinib make important interactions with the Abl kinase domain. These groups also make the shape of nilotinib very different from that of imatinib. Nilotinib also binds to the kinase through a large number of weak van der Waals interactions.[11]

Resistance

Nilotinib has shown effect against most mutations (32/33) that are associated with imatinib resistance but the T315I mutant remains resistant to nilotinib.[10][11][15] It's ineffectiveness against the T315I mutant seems to be a consequence of the loss of an H-bond interaction between threonine-O and aniline-NH on nilotinib and a steric clash between the isoleucine-methyl group and 2-methylphenyl phenyl group of nilotinib.[10] On the other hand, resistance to nilotinib is associated with a limited spectrum of Bcr-Abl kinase mutations that mostly affect the P-loop and T315I. However all mutations except T315I were effectively suppressed by increasing nilotinib concentration.[15] Although nilotinib is more potent than imatinib it is possible that its specific mode of binding to Abl may make other sites vulnerable to new kinds of drug resistance.[16]

Dasatinib (BMS-345825)

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Development Dasatinib is a thiazolylaminopyrimidine developed as the hydrochloride salt. It was discovered with a program directed towards immunosuppressive drugs and is 325-fold more potent against cells expressing wild type Bcr-Abl than imatinib.[10][16] Dasatinib is a multi targeted inhibitor of Bcr-Abl and Src family kinases.[10][16] It also has inhibitory activity against additional downstream kinases.[16][18]

Binding Dasatinib binds to Abl with less stringent conformational requirements than imatinib so it exhibits increased potency but reduced selectivity compared to imatinib.[16] Dasatinib exclusively binds the active conformation of Abl kinase, contrary to most TKIs.[6] Compounds that target the active conformation have been identified but the binding site in all the hundreds of human protein kinases is very similar. Therefore, there is a considerably greater scope for dissimilarities between the inactive conformations so the efforts to discover highly selective kinase inhibitors are being directed towards molecules that bind to the inactive conformation.[10]

Dasatinib has some structural elements in common with nilotinib, in particular the juxtaposition of the aminopyrimidine and the carboxamide groups. The aminothiazole segment of dasatinib makes a bi-dentate H-bonding interaction with the backbone CO and NH of Met-318 and the amide-NH makes an H-bond with the side chain oxygen of Thr-315.[10]

Resistance

Since dasatinib is an inhibitor of Src family kinases it can overcome resistance because of Src family kinase activation. Because it does not bind to Bcr-Abl with the same stringent conformational requirements as imatinib it can inhibit all Bcr-Abl kinase domain mutants except for T315I. Dasatinib is also not a substrate of multidrug P-glycoprotein efflux pumps like imatinib. Because of this dasatinib may be active in some patients after failure with both imatinib and nilotinib.[16] Although dasatinib is much more potent than imatinib it is possible like with nilotinib that its specific mode of binding to Abl may lead to new vulnerable sites that could confer new kinds of drug resistance. Mutations have been found on Phe317 so that is a potential vulnerable site for this drug.[16]

Drugleads

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While the first and second generations TKIs are delivering promising results, new mutations of Bcr-Abl TK are still being discovered and some old go unconquered. Those mutations, new and old, are the drive for pharmaceutical companies to continue the search for novel ways to treat patients with CML. In 2010 there were quite a few drugs in development who are either refining current treatments or promising great improvements in efficacy.

Bosutinib (SKI-606)

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Development

Bosutinibs structure is based on a quinoline scaffold and is structurally related to the AstraZeneca quinazoline template.[10] Src kinase dependent yeast screen led to characterization of a 4-anilino-3-quinolinecarbonitrile as an Src inhibitor. Combination of the features of this hit and a related compound and attachment of solubilizing groups led to the discovery of bosutinib. It was suggested to be an Abl kinase inhibitor and when tested as such it turned out to be slightly more potent against Abl then Src (IC50 1,4 nM vs. 3,5 nM).[19] Bosutinibs activity was first described in 2001 and it was disclosed as an Abl kinase inhibitor in 2003. At first it was believed that bosutinib was a selective Src kinase inhibitor but now it is known that its kinase inhibition profile is far less restricted than originally thought. Bosutinib inhibits Src, Abl and a wide range of both tyrosine and serine-threonine kinases.[19]

Resistance

Bosutinib inhibited cells expressing a variety of mutations, some of which led to imatinib resistance, but the T315 mutation was completely resistant to bosutinib.[10][19] In contrast to imatinib, nilotinib and dasatinib, bosutinib is not an efficient substrate for multidrug resistance (MDR) transporters that promotes efflux of foreign molecules from cells. Bosutinib even inhibits these transporter proteins in higher concentrations.[19]

Ponatinib (AP24534)

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ARIAD Pharmaceuticals, Inc. announced on September 10, 2010 that ponatinib, an orally active Bcr-Abl TKI effective against the T315I mutation had been approved for a phase II clinical trial.[20]

The road to discovery can be linked to one of the first of Ariads ATP competitive dual Src/Abl inhibitors AP23464. AP23464 was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. The substance potently inhibits, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations, but not the T315I mutation.[21]

Development

Ponatinib development history

Ariad used the highly potent druglead, AP23464 to further investigate inhibitory possibilities of purine cored templates for dual Src/Abl inhibitors. Searching for substances effective on the inactive conformation of Abl they first replaced the side chain bound to the nitrogen on the purine core. They used a diarylamide structure that was known to have a high affinity to the inactive conformation by forming crucial hydrogen bonds and filling hydrophobic pockets on the kinase. Furthermore they determined that the cyclopentyl group on the purine core clashed with a glycine rich P-loop in that confirmation and thus removed it from the molecule. Then with in vitro testing on inhibitory activity and in vivo oral absorption assays they discovered that a more lipophilic, amide bound, cyclopropyl group on C6 on the purine core displayed both satisfactory pharmacokinetics and efficacy. Finally modifications on the diarylamide side chain by adding imidazole appendages were inspired by then newly released nilotinib structure. Those modifications resulted in what was called AP24163. During this development cycle several substances were tested against cells transfected with T315I mutated Bcr-Abl kinase, and to their surprise AP24163 demonstrated reasonable inhibitory action on top of potent inhibition of native Bcr-Abl.[22]

Following up on that breakthrough Ariad began further research to increase the efficacy of compound AP24163 against the T315I mutation. Docking of the molecule into the ATP binding site of T315I mutated Bcr-Abl kinase revealed that the expected steric clash with isoleucine was not present due to a lesser sterically demanding vinyl linkage between the purine core and the diarylamide side chain compared to other TKIs. The first step was to try and find an even less sterically demanding structure. First an acetylene linkage was tested, that resulted in higher potency but unfavorable pharmacokinetics. Then they opted for a more stable 2-butyne linkage. To achieve this linkage they used imidazol[1,2-a]pyridine core as a starting material for a Sonogashira reaction. The pharmacokinetics were still poor. When developing AP24163 adding a cyclopropane side chain on C8 in the purine core resulted in favorable pharmacokinetics. With that in mind several different side chains were tested but interestingly the best results were obtained with no side chain at all resulting a substance with satisfactory pharmacokinetics, but now potency against T315I had been reduced. The first step in increasing the potency was to look at other TKI’s. Imatinib has a terminal methyl piperazine group which has been shown to form a hydrogen bond with the carbonyl oxygen atom of residue Ile-360 in the activation loop of the Abl kinase. The piperazine ring is also a common solubilizing group that could further improve the pharmacokinetic properties of the molecule. Those speculations were confirmed with a 2 fold increase in inhibitory action against Bcr-Abl T315I mutated kinase and the silver lining was that the protein binding of the substance named 19a appeared to have decreased, allowing for smaller doses with the same potency. 19a exhibited good oral pharmacokinetics in both mice and rats. Even so the ClogP value was 6.69 and in attempts to reduce 19a’s lipophilicity tweaking of the structure resulted in substitutions of a carbon atoms on the imidazo[1,2-a]pyridine core. The tweaking resulted in what is now known as ponatinib.[23]

Ponatinib in it's binding site

Binding

X-ray crystallographic analysis of ponatinib and T315I Bcr-Abl mutated kinase display that the imidazo[1,2b]pyridazine core rests in the adenine pocket of the enzyme. The methylphenyl group occupies a hydrophobic pocket behind I315, the ethynyl linkage forms favorable van der Waals interactions with the amino acid and the trifluoromethyl group binds to a pocket induced by the inactive conformation kinase. Also in the conformation of the kinase that ponatinb rests in, additional favorable van der Waals interactions between the drug and Tyr-253 and Phe-382. Five hydrogen bonds are generated, with the backbone of Met-318 in the hinge region, with the backbone of Asp-381, with the side chain of Glu-286 and the protonated methylpiperazine with the backbone-carbonyl atoms of Ile-360 and His-361.[24]

With this structure ponatinib has been shown to have a relatively broad kinase specificity profile which can probably be linked to the linearity of the linkage section of the molecule. With this linear structure the drug appears avoid steric clashes with hydrophobic TK gatekeeper residues. Despite, or even because of this, ponatinib is a potent drug and targets, not only, most of the known mutations on the Bcr-Abl TK but also the infamous T315I mutation. This mutation is emerging as a common pathway to failure of both first and second line treatments. Unlike other T315I targeting inhibitors in development, ponatinib is not targeting Aurora kinase which clearly distinguishes it from them and emphasis the significance of this discovery.[24]

Bafetinib (INNO-406)

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With the emerging resistance to imatinib treatment after its launch alternative treatment was highly sought after. Bafetinib was the offspring of an attempt to create a more potent drug than imatinib, with efficacy against various point mutations in the Bcr-Abl kinase, with fewer adverse effects and with narrower kinase spectra, namely just Lyn and Bcr-Abl.[25]

Development

In the search for the substance that fitted the criteria mentioned above the crystal structure of imatinib bound to Abl was examined. There they spotted a hydrophobic pocket around the phenyl ring adjacent to the piperazinylmethyl group of imatinib. In their attempts to utilize this pocket to increase efficacy they added various hydrophobic groups including a single fluoro, bromo and chloro substituents. In the end it was a trifluoromethyl group at position 3 displayed the best results with approximately 36 fold improvement over imatinib. The addition of this hydrophobic group needed to be countered to sustain the solubility of the substance. Then they looked to the pyridine ring on the imatinib structure and how it interacted with the kinase. In close proximity of the ring is Tyr-236, according to the crystal structure of imatinib kinase complex, which suggested that there was little or no room for a larger group. With that in mind the substituted the pyridine ring for a more hydrophilic pyrimidine ring. This modification increased the solubility and the efficacy was practically the same, even slightly greater. Finally to try and improve the important hydrogen bonding of the piperazine ring of imatinib with Ile-360 and His-361 they introduced pyrrolidine and azetidine derivatives. The most promising substance, in regards to pharmacokinetics and efficacy, from that final modification was labeled NS-187.[9]

Binding

Bafetinib in it's binding site

Due to the structural similarities with imatinib and bafetinib the binding to Bcr-Abl is also quite similar. The only notable difference is the hydrophobic interaction between the trifluoromethyl group and the hydrophobic pocket created by Ile-293, Leu-298, Leu-354, and Val-379. This group can also be linked to the specificity of bafetinib as the binding site on Lyn is almost identical to the binding site on Bcr-Abl.[26]

Bafetinib has its place in therapy as it is effective against most imatinib resistant mutations, not including T315I, and some dasatinib resistant mutations. Bafetinib has more affinity for Bcr-Abl than nilotinib but less than dasatinib, but it only targets Bcr-Abl and Src family kinases Lck and Lyn with unrivaled specificity, which suggests the possibility of fewer adverse effects.[27] So that there is no surprise that CytRx has bafetinb in phase II clinical trial as a treatment for leukemia as of May 2010.[28]

1,3,4 thiadiazole derivatives

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Some interest has been with thiazol and thiadiazole derivatives and their ability to inhibit Bcr-Abl TKs.

Development

One Italian research group discovered through digital screening that commercially available thiadiazole derivatives displayed moderate inhibitory action on both Abl and Src kinases.[29] Using a 1,3,4 thiadiazol core and trying different groups or molecules on the benzene rings hey produced a few substances with inhibitory properties. The flexibility of the core allowed for a number of confirmations for the substance to bind to the ATP binding site of the Abl kinase, though all of them bound to the kinase’s active form.[29]

They further studied the binding and realized that position of the sulfur that binds to the toluene structure played an important role in regard to Abl binding and also that the only one of the nitrogens one thiadiazole formed a hydrogen bond. Furthermore, computer analysis of the structure detailed that the amide connected benzene-ketone could be substituted for a more favorable thiophene ring.[30] Though it has to be noted that this analysis was done with comparing the crystal structure of Abl and dasatinib, which is the inactive conformation of Abl. Even so, with this knowledge gathered from docking and structure analysis they came up with a substance with a high affinity to Abl, it was called 14.

Binding

The binding of substance 14 is partly similar to dasatinib, the aminothiazole segment of substance 14 makes a bi-dentate H-bonding interaction with the backbone CO and NH of Met-318 while the methoxy-benzene falls nicely into a hydrophobic pocket created by Val 256, Ala 253, Lys 271 and Ala 380.[30]

The possibility to make Bcr-Abl TKI’s from thiazole cores seems quite possible and even apparent with regards to dasatinib but the question yet to be answered is if this research will just lead to a dasatinib analog or a novel way to inhibit TKIs.

Summary

[edit]
Drug Structure H-bonds H-bonding amino acids Binding confirmation Discovery Status on november 4th 2010
Imatinib (STI571) 6 Met-318, Thr-315, Glu-286, Asp-381, Ile-380, His-361 Inactive Drug screening Marketed as first line therapy
Nilotinib (AMN107) 4 Met-318, Thr-315, Glu-286, Asp-381 Inactive Rational drug design Marketed as second line therapy
Dasatinib (BMS-345825) 3 Met-318, Thr-315 Active Rational drug design Marketed as second line therapy
Bosutinib (SKI-606) - - Inactive Rational drug design Phase III clinical trials
Ponatinib (AP-24534) 5 Met-318, Asp-381, Glu-286, His-381, Ile-380 Inactive Rational drug design Phase II clinical trials
Bafetinib (INNO-406) 6 Met-318, Thr-315, Glu-286, Asp-381, His-361, Ile-360 Inactive Rational drug design Phase II clinical trials


Current Status

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In the near future, there is hope for better treatment results in TKI-resistant CML, based on the availability of second generation TKI and other drugleads. Imatinib still remains the standard frontline TKI, but more potent Bcr-Abl TKIs are available. Two of these drugs, nilotinib and dasatinib, are approved for the treatment of imatinib resistant or intolerant CML. The first line data for these compounds are encouraging and suggest that one or both of them may replace imatinib as a frontline standard TKI in the future.[31]

See also

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References

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  1. ^ a b c d e f g h i j k An, X.; Tiwari, A.; Sun, Y.; Ding, P.; Ashby Jr, C.; Chen, Z. (2010). "BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review". Leukemia research. 34 (10): 1255–1268. doi:10.1016/j.leukres.2010.04.016. PMID 20537386.
  2. ^ a b c d e f g Bixby, D., Talpaz, M. (2009). "Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance". Hematology: 461-476.
  3. ^ a b c Manley, P.W., Cowan-Jacob, S. W., Buchdunger, E., Fabbro, D., Fendrich, G., Furet, P., Meyer, T. and Zimmermann, J. (2002). "Imatinib: a selective tyrosine kinase inhibitor". European Journal of Cancer: S19-S27.
  4. ^ Shawver, L. K., Slamon, D. and Ullrich, A. (2002). "Smart drugs:Tyrosine kinase inhibitors in cancer therapy". Cancer Cell: 117-123.
  5. ^ a b Druker, B. J. and Lydon, N. B. (2000). "Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia". The journal of Clinical Investigation: 3-7.
  6. ^ a b c d Eck, M.; Manley, P. (2009). "The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl". Current opinion in cell biology. 21 (2): 288–295. doi:10.1016/j.ceb.2009.01.014. PMID 19217274.
  7. ^ a b Buchanan, S. G. (2003) "Protein structure: discovering selective protein kinase inhibitors". Targets: 101-108.
  8. ^ Mandal, S.; Moudgil, M.; Mandal, S. (2009). "Rational drug design". European Journal of Pharmacology. 625 (1–3): 90–100. doi:10.1016/j.ejphar.2009.06.065. PMID 19835861.
  9. ^ a b c d Asaki, T.; Sugiyama, Y.; Hamamoto, T.; Higashioka, M.; Umehara, M.; Naito, H.; Niwa, T. (2006). "Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors". Bioorganic & Medicinal Chemistry Letters. 16 (5): 1421–1425. doi:10.1016/j.bmcl.2005.11.042. PMID 16332440.
  10. ^ a b c d e f g h i j k l Manley, P.; Cowan-Jacob, S.; Mestan, J. (2005). "Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia". Biochimica et Biophysica Acta. 1754 (1–2): 3–13. doi:10.1016/j.bbapap.2005.07.040. PMID 16172030.
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