When was imatinib developed

In some of these patients, there was also cytogenetic remission, meaning that the Philadelphia chromosome was no longer found in their blood cells. As Druker noted, "That was virtually unheard of in a phase I clinical trial. It was absolutely incredible to see this unfold" Taubes, Subsequent clinical trials produced results just as astonishing.

In a way, Gleevec is an exceptional case, and the same success is not likely to be achieved with other cancers any time soon. Unlike most other cancers, which are caused by a multitude of complex interacting genetic and environmental factors and therefore have many targets, CML is caused by a single aberrant protein related to a consistent chromosomal translocation.

Scientists were thus able to focus all of their efforts on this single target. Nonetheless, the Gleevec story is no less an excellent and, some would say, beautiful example of how knowledge of the biological functioning of a cell can lead to life-saving medical treatment. Cameron, D. A slow saga of success. Daley, G. Science , — doi Druker, B. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

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Pray, Ph. Citation: Pray, L. Nature Education 1 1 How do scientists develop new treatments for disease? With Gleevec, a remarkable cancer drug, the approach was to target the disease at the cellular and subcellular level.

Aa Aa Aa. Some say it's a miracle drug. Others call it a silver bullet. Gleevec, also marketed internationally as Glivec and sometimes referred to by its chemical name imatinib, entered the medical world with a bang. This medication was initially approved for use by the U. Food and Drug Administration FDA in for the treatment of chronic myelogenous leukemia CML , a rare form of cancer that affects certain types of white blood cells. Since its initial approval, Gleevec has also been approved for use in patients with several types of gastrointestinal tumors.

Currently, scientists continue to study the drug's effectiveness not only in various cancers, but also in other diseases, such as stroke Su et al. But just how effective is Gleevec, especially when it comes to CML, and what is its mechanism of action? In the early s, a screening for protein kinase C PKC inhibitors was carried out and led to the identification of a phenylaminopyrimidine derivative as potential lead compound with high prospective for diversity, allowing simple chemistry to produce more potent and selective molecules against several kinases [ 14 ].

Various functional groups were then tested as substituents in the phenyl ring, until the presence of an amide group was found to confer inhibitory action against tyrosine kinases. Furthermore, analysis of structure-activity relationships evidenced that a substitution in position 6 of the diaminophenyl ring abolished the activity against PKC.

Conversely, the addition of a methyl group in an ortho position to the amino group increased selectivity for Bcr-Abl. However, the resulting molecule still showed poor oral bioavailability and solubility in water, which were considerably improved by the introduction of an N -methylpiperazine group.

Nevertheless, in spite of the abovementioned improvements and of the increased affinity of the resulting molecule for its target, the N- methlypiperazine addition would have generated an aniline moiety in the structure. To abolish its mutagenic potential, the abovementioned amide group and a spacer benzene ring were introduced [ 14 ]. These structural developments led to the production of imatinib STI Fig. Docking studies and X-ray crystallography evidence that imatinib interacts with its target through binding the hinge region in its entire width [ 17 ].

Chemical optimization and functions of imatinib structure. The phenylaminopyrimidine derivative lead compound is indicated in black. Imatinib was therefore developed as optimized Bcr-Abl oral inhibitor.

Imatinib consists in a typical bisarylanilino core comprising a phenyl ring on one side and a pyridine-pyrimidine moiety on the other side, possessing a benzamide-piperazine group in the meta-position of the aniline-type nitrogen atom Fig.

The former is shielded from the solvent in a hydrophobic cage delimited by Tyr of the P-loop which is kinked during the inactive phase , Phe of the activation loop, together with Leu, Phe and Leu residues; the latter preeminently establishes VdW interactions with the following Bcr-Abl residues: Val and Met of the C- lobe, Asp of the DFG motif, and Ile and His of the catalytic loop [ 11 ].

In fact, if one of these bonds and consequently its energetic contribution gets lost, free energy of dissociated state becomes highly competitive against that of the bound state, thus justifying the missed interaction between imatinib and the mutated kinase due to less favorable thermodynamic factors: that underlies resistance.

Imatinib treatment fails in approximately one third of patients [ 18 ]. Underlying mechanisms of resistance are classically divided into two types: Bcr-Abl-dependent and Bcr-Abl-independent mechanisms. The former, instead, are mainly due to point mutations of Bcr-Abl that alter inhibitor binding or conformational changes; nevertheless, a residual amount of Bcr-Abl-dependent resistances are also due to gene amplification or hyperexpression [ 19 ].

Since the vast majority of cases are due to point mutations, new inhibitors have been developed with a rational drug design approach aimed at overriding resistances by loosening conformational and binding requirements without losing specificity. Second-generation inhibitors solve almost the entirety of mutations except for TI. The substitution of the gatekeeper residue frustrates the action of inhibitors through two potent mechanisms: break of a H-b and strong stabilization of the active DFG-in conformation.

This consistent obstacle has been overcome only thanks to third-generation inhibitors [ 20 ]. In order to break through mutations, several second-generation TKIs have been developed and approved for clinics, i. This result has been reached starting from the structure of imatinib by inverting the amide linking group, by replacing the piperazine ring with 3-methylimidazole, and by adding trifluoro-methyl group to the anilinocarbonyl substituent, in order to increase the number of VdW interactions Fig.

Therefore, energetic contribution to the total of each H-b decreases, avoiding impairment of inhibitor binding in case of mutation of key residues involved in H-b interactions, although the overall number of H-bs was kept unchanged. In spite of these modifications, less stringent binding requirements did not compromise selectivity and potency of nilotinib, which conversely are even increased when compared to those of imatinib IC 50 values of 10—25 and — nM, respectively—see Table 1. As previously told, nilotinib is active against DFG-out conformation only, and this accounts for TI resistance.

Interestingly, nilotinib is not substrate of neither influx transporter nor efflux P-glycoprotein pump, unlike imatinib and, therefore, is not sensitive to Bcr-Abl-independent mechanisms of resistance [ 24 ]. Chemical structures are here represented in color code with regard to analogous groups of different tyrosine kinase inhibitors green: core structure; red and blue: substituents group.

Compared to imatinib, dasatinib enables patients with chronic phase CML to achieve faster and deeper treatment responses i. Structurally, the core phenyl ring has been replaced by an aminothiazole group which occupies the adenine pocket of Abl Fig. The pyridine group of imatinib is instead replaced by a hydroxyethyl piperazine, which remains solvent-exposed also after Bcr-Abl binding.

Dasatinib is a smaller molecule than imatinib and it establishes less interactions with its targets: nuclear magnetic resonance studies have evidenced that dasatinib binds Bcr-Abl very versatilely, in both active and inactive conformations [ 26 ].

However, the free inactive DFG-out conformation has a higher entropy than the active conformation: the drop in entropy is less pronounced after dasatinib binding if the target is active, with enthalpy variation being very similar in both conformations.

Thus, free energy decreases more in case of binding during DFG-in phase, which is therefore preferentially inhibited by dasatinib, because it is thermodynamically favored. Consequently, several conformation-altering mutations, except for TI, are susceptible to dasatinib action, anyway [ 27 ].

Bosutinib SKI has a more different structure Fig. The quinoline central core required the addition of a hydrophilic protonable N -methylpiperazino moiety.

Though it is not effective against TI mutation and does not show total selectivity for Bcr-Abl see Table 1 , it has the important advantage of being not efficiently excreted by multidrug resistance transporters [ 29 , 30 ]. Bosutinib is currently approved as second-line treatment of CML [ 21 ]. Recent data suggest it can be an important alternative to imatinib for previously untreated patients with chronic phase CML, given its earlier and higher rate of responses In fact, isoleucine in position complicates Bcr-Abl switching to inactive conformation and H-b formation with DFG-out inhibitors.

Nonetheless, ethynyl linkage of ponatinib has indeed been inserted to accommodate isoleucine side chain without any steric interference also in inactive conformation DFG-out [ 32 ].

Structurally Fig. Besides, instead of the pyridine-pyrimidine group of nilotinib, ponatinib has a terminal imidazo[1,2-b]pyridazin portion in the same position to optimize H-b formation within the hydrophilic pocket in which it gets accommodated. Other bonds are similar to those of nilotinib and so abundant that kinase point mutations have less effect on the overall binding affinity and the potency of the drug see Table 1 , ponatinib IC 50 are the lowest for almost every Bcr-Abl point mutation [ 33 ].

Other molecules have been effectively tested since the advent of second-generation inhibitors, but have not entered common clinical practice for neither CML nor ALL, yet. Namely, they are bafetinib, rebastinib, tozasertib, danusertib, HG, GNF-2 and -5, and 1,3,4 thiadiazole derivatives. Furthermore, it is highly probable that new in silico and in vitro evidences may lead to new molecules to enter the clinics in the near future to overcome persistent resistances. Bafetinib INNO development was aimed at extending the susceptibility spectrum of mutations to TKIs and increasing selectivity towards Bcr-Abl to reduce clinical adverse reactions during treatment, e.

That was pursued by increasing hydrophobic properties of the benzamide ring of imatinib Fig. In the meantime, in light of X-ray crystallography predictions, the pyridine group of imatinib was replaced by a more hydrophilic pyrimidine ring, thus increasing aqueous solubility without impairing binding properties and potency against Bcr-Abl IC 50 71 nM [ 17 ]. Finally, the dimethylaminopyrrolidine portion took the place of the N-methylpiperazine ring, favoring H-b formation [ 36 ].

Rebastinib DCC is a non-competitive conformational control inhibitor, designed to overcome Abl gatekeeper mutations, mainly TI, that impede the occurrence of the DFG-out conformation and the inhibitory action of both first- and second-generation inhibitors [ 39 ]. It stabilizes a fundamental bond for inactive conformation between Glu and Arg, regardless gatekeeper mutations.

Structurally, the fluoro-substituted phenyl central core, possessing a ureic linker in ortho to the halogen atom, is also bound to a carboxamide-substituted pyridine on one side, and to a pyrazole, bearing 4- tert -butyl and 1- 6-quinolinyl substituents, on the other side Fig. Crystallography evidenced that the ureic and the carboxamide-pyridine groups establish five H-bs mainly with the aforementioned Glu and Arg residues, whereas the rest of the molecule optimizes VdW interactions with a hydrophobic cluster of amino acids, forcing out the DFG motif from the catalytic site.

In the case of TI mutation, the hydrophobic interactions are even enhanced, justifying sensitivity to rebastinib in cellular assays with clones displaying this mutation IC 50 13 versus 19 nM for unmutated Abl [ 40 ].

However, it is much less active against P-loop EV mutation IC 50 nM , possibly due to destabilization of Bcr-Abl inactive conformation, but its molecular mechanism deserves further characterization [ 39 ].

Clinically, although rebastinib showed efficacy of 40 CML patients, 8 complete hematologic responses were achieved, 4 of which had a TI mutation [ 41 ], benefit has been considered insufficient to justify continued development against leukemias since the advent of ponatinib, to date. Peculiarly, Aurora kinases are inhibited in their inactive state, whereas Bcr-Abl, both WT and mutant TI, in active conformation [ 37 ].

Indeed, co-crystal structures evidenced four H-bs established by the aminopyrazole pyrimidine inhibitor Fig. Further developments or combinational regimens seem to be amply justified for this promising compound. Similar to dasatinib and tozasertib, it is an ATP competitor for the active form of Bcr-Abl, as evidenced by crystallographic data [ 47 ]. Its pyrrolopyrazole core Fig. No key interactions are established with the gatekeeper residue.

Clinically, danusertib has shown acceptable dose-dependent toxicities and promising activity in advanced and resistant ALL and CML patients within a phase II trial 4 out of 29 patients with accelerated or blast phase CML responded, all 4 with TI Bcr-Abl [ 49 ], paving the way for further preclinical and clinical advancements.

HG is a hybrid compound, designed by superposition of nilotinib and dasatinib structures. The master concept of condensing in a unique molecule the advantages of a combinational therapy, i. Structurally, the aminothiazole moiety of dasatinib is condensed to a pyridine ring and the resulting portion is linked to the phenyl-benzamide group of nilotinib Fig.

In fact, this structural arrangement results in a very accommodating inhibitor molecule for the gatekeeper residue, showing activity also against TI Bcr-Abl in cellular assays IC 50 nM, less than threefold higher than for WT, i.

Furthermore, the target selectivity spectrum is narrower than that of ponatinib at a high-throughput screening [ 50 , 51 ], suggesting less adverse reactions than ponatinib at a clinical level, especially those related to cardiovascular toxicity.

However, no clinical data are currently available, nor are there ongoing trials, to the best of our knowledge. Recently, new state-of-the-art molecules have been designed and tested at a preclinical level to sensitize TI mutation to first and second-generation TKIs. Genetic, nuclear magnetic resonance, crystallography, mutagenesis and mass spectrometry studies identified GNF-2 Fig. They bind the myristylation site of C- lobe inducing a forced conformational change of the kinase to inactive state, even if its gatekeeper residue is mutated [ 53 ].

Co-administration of a classical inhibitor with these compounds may therefore be effective also against TI mutant. However, mutations around the myristate binding site, e.

This raises critical issues on some compound mutations of Bcr-Abl, i. A further way to inhibit Bcr-Abl could be paved by 1,3,4-thiadiazole derivatives, such as compound 2 Fig. Indeed, flexibility of its core is supposed to allow several conformations of the substances to bind the ATP site of Bcr-Abl active state [ 55 ].

The development of targeted inhibitors started from a high-throughput screening to find out a leading pharmacophore that includes compounds able to bind and block the chimeric kinase, by impeding ATP binding in a competitive manner [ 16 , 17 ]. After its rational development, according to structure-activity relationship analysis and enzymatic assays [ 16 ], imatinib was optimized and rapidly approved for the clinic [ 5 ].

Actually, the IRIS trial clearly demonstrated that imatinib presented much higher effectiveness and reduced toxicity if compared to the standard of care of that time, i. Although the radical increase in mean survival, new mutations and forms of resistance came upon in common clinical practice [ 57 ], requiring further development of inhibitors, similar to the process that led from the parent compound to imatinib. By means of imatinib modification or exploitation of totally different molecular scaffolds, several second- and third-generation TKIs were developed.

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