Anticancer Drug Dasatinib Research Articles

Quantum chemical treatment, electronic energy in various solvents, spectroscopic, molecular docking and dynamic simulation studies of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide: A core of anticancer drug

The titled molecule 2-Amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (ANMC) is a core of anticancer drug dasatinib (leukemia). Its derivatives exhibited bioactivity against breast cancer. Experimentally, the titled compound was described using NMR (1H NMR and 13C NMR), FTIR and UV–visible spectroscopy. The results were compared with the theoretical predictions, showing good agreement such as theoretical NH vibrations showed symmetric stretching and asymmetric stretching at 3429 and 3440 cm−1 respectively, λmax values appear at 305 nm for experimental and 307.75 nm for theoretical observations in acetone medium. Hirshfeld surface analysis well described the secondary internal and external interactions obtained like dnorm and di ranges −1.8551 to 1.4590 and 0.0918 to 2.6756 respectively. Comparing UV–visible spectra obtained in various solvents with the calculated TD-DFT results revealed minimal solvent effects. Molecular electrostatic potential (MEP) map and Fukui functions were employed, which indicated reactive sites of the molecule and the obtained order of nucleophilic reactivity was C16 > C2 > C8 > Cl1 > C22 > C21. The bioactivity profile probability of ANMC was theoretically explored by calculation of electrophilicity index and drug-likeness. Molecular docking of the ANMC molecule was performed with ten receptors to obtain the best ligand–protein interaction and the minimum binding energy obtained was −8.0 kcal/mol. Biomolecular stability of ANMC was investigated by Molecular Dynamic Simulation (MDS). And also the analysis of free energies showed strong interactions between the ligand and the protein.

Investigating the effect of polyvinylpyrrolidone matrix on surface characteristics and dissolution rate of anticancer drug dasatinib

AbstractDasatinib (DAS) is a second‐generation tyrosine kinase inhibitor used in the treatment of Philadelphia chromosome‐positive chronic myeloid leukemia and acute lymphoblastic leukemia. Nevertheless, this drug is hindered by poor gastrointestinal absorption and limited bioavailability, primarily attributable to its low aqueous solubility. To improve its properties, solid dispersions of DAS within a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP) are prepared by cogrinding in a vibrational ball mill at various drug‐to‐polymer ratios. The prepared solid dispersions are thoroughly characterized by several methods to verify the drug's amorphization and enhanced wettability as a result of successful mechanochemical activation. Fluidized bed melt granulation and traditional tableting are used to prepare tablets of 8 mm diameter with strictly defined aimed properties. Characterization of tablets includes testing their hardness, disintegration, and in vitro dissolution. The in vitro release profiles reveal a significant improvement in the release rate of DAS from tablets containing solid dispersion with the highest polymer ratio when compared with those containing untreated DAS or solid dispersions with a low polymer ratio. The results confirm the significant effect of the PVP ratio in solid dispersions on the surface characteristics and dissolution rate of DAS.

Synthesis, DFT, in silico anticancer, ADME and toxicity prediction study of (E)-2-(2-(3,4-dihydronaphthalen-1(2H)- ylidene)hydrazineyl)-4-(4-methoxyphenyl)thiazole

In the current paper, we describe computational molecular modeling to investigate the quantum chemical, spectroscopic, MESP and in-silico Anticancer, ADME and toxicity study of (E)-2-(2-(3,4-dihydronaphthalen-1(2H)-ylidene)hydrazineyl)-4-(4-methoxyphenyl)thiazole by one pot three component reaction. DFT method with B3LYP/6-311G(d,p) level was used to optimize the geometry, molecular electrostatic potential (MESP), Mulliken charges and vibrational assignments. The UV-Vis assignments, frontier molecular orbital (FMO), electronic parameters, and global descriptor were studied using the TD-DFT method with CAM-B3LYP/6-311G(d,p) level. In-silico anticancer study revealed favorable binding interaction with an excellent docking score comparable to the anticancer drug Dasatinib. The molecular docking study found that, target 4xt2 receptor’s amino acid residues VAL422B, LEU407D, MET426D, TYR327A, GLN421B, SER424B, and LEU423D play a vital role. The title compound has the requisite toxicity and ADME profiles, and it has the potential to be therapeutic.

A disposable electrochemical sensor based on single-walled carbon nanotubes for the determination of anticancer drug dasatinib

Dasatinib is an anticancer drug that treats acute lymphoblastic leukemia, chronic myelogenous leukemia, and prostate cancer with several side effects. In this research, we suggest nanoparticle-modified screen-printed electrodes (SPCEs) as disposable electrochemical sensors for fast quantification of dasatinib in pharmaceutical formulations. Carbon nanotubes, single-walled carbon nanotubes (SWCNT), graphene, and graphene oxide-modified SPCEs were characterized by scanning electron microscopy. The study also recommends SWCNT-modified SPCEs as the best-performing electrode for determining dasatinib, demonstrating an excellent boosting effect on the oxidation response of dasatinib. This was accomplished using the square-wave voltammetry method. After optimization of the pH condition, pH 5.0 Britton–Robinson buffer, SWCNT-modified SPCEs demonstrated 94% recovery with optimum electro-oxidation activity. The oxidation currents exhibited linear relation with dasatinib concentration in the 0.1–100 µM. Based on the results, a limit of detection of 0.06 µM was obtained in the standard solution. The SWCNT-modified SPCEs have been applied to analyze dasatinib in pharmaceutical tablet samples. The demonstrated performance beats all comparable standard analytical tools and presumably may be used for general drug quantitation in pharmaceutical tablets.Graphical abstract

Complete reconstruction of dasatinib unbinding pathway from c-Src kinase by supervised molecular dynamics simulation method; assessing efficiency and trustworthiness of the method

Over the past years, rational drug design has gained lots of attention since employing it gave the world targeted therapy and more effective treatment solutions. Structure-based drug design (SBDD) is an excellent tool in rational drug design that takes advantage of accurate methods such as unbiased molecular dynamics (UMD) simulation for designing and optimizing molecular entities by understanding the binding and unbinding pathways of the binders. Supervised molecular dynamics (SuMD) simulation is a branch of UMD in which long-duration simulations are turned into short simulations, called replica, and a specific parameter is monitored throughout the simulation. In this work, we utilized this strategy to reconstruct the unbinding pathway of the anticancer drug dasatinib from its target protein, the c-Src kinase. Several unbinding events with valuable details were achieved. Then, to assess the efficiency and trustworthiness of the SuMD method, the unbinding pathway was also reconstructed by conventional UMD simulation, which uncovered some of the limitations of this method, such as limited sampling of the active site and finding the metastable states in the unbinding pathway. Furthermore, in times like these, when the world is desperate to find treatments for the Covid-19 disease, we think these methods are of exceptional value. Communicated by Ramaswamy H. Sarma

Pan-Cancer Prognostic, Immunity, Stemness, and Anticancer Drug Sensitivity Characterization of N6-Methyladenosine RNA Modification Regulators in Human Cancers.

N6-methyladenosine RNA modification plays a significant role in the progression of multiple tumorigenesis. Our study identified the imperative role of m6A regulators in the tumor immune microenvironment, survival, stemness score, and anticancer drug sensitivity of pan-cancer. The Wilcox test was to identify the differential expression between 17 m6A regulators across 33 TCGA cancer types and their normal tissues from UCSC Xena GDC pan-cancer. Survival analysis of m6A-related regulators in 33 TCGA cancer types was identified using the “survival” and “survminer” package. The Spearman correlation test and Pearson correlation test were used to identify the correlation relationship between m6A regulators expression and tumor microenvironment, tumor stem cell score, and drug sensitivity of anticancer drugs. ConsensusPathDB was used for exploring m6A regulators functional enrichment. The 17 (METTL3, WTAP, METTL14, RBM15, RBM15B, VIRMA, HNRNPC, HNRNPA2B1, YTHDC1, ZC3H13, YTHDF1, YTHDC2, YTHDF2, IGF2BP3, IGF2BP1, FTO, and ALKBH5) m6A regulators were differentially expressed in 18 TCGA cancer types and adjacent normal tissues. Correlation analysis indicated that the relationship between the expression of 17 m6A regulators and tumor microenvironment indicated that the higher expression of m6A regulators, the higher the degree of tumor stem cells. The anticancer drug sensitivity analysis indicated that ZC3H13 expression had a positive relationship with anticancer drugs such as selumetinib, dabrafenib, cobimetinib, trametinib, and hypothemycin (p < 0.001). YTHDF2 expression was significantly negatively correlated with the anticancer drug dasatinib (p < 0.001). The pan-cancer immune subtype analysis showed that the 17 m6A regulators were significantly different in immune subtype C1 (wound healing), C3 (inflammatory), C2 (IFN-gamma dominant), C5 (immunological quiet), C4 (lymphocyte depleted), and C6 (TGF-beta dominant) (p < 0.001). Our study provides a comprehensive insight for revealing the significant role of m6A regulators in the tumor immune microenvironment, stemness score, and anticancer drug sensitivity of human cancers.

A voltammetric study on drug-DNA interactions: Kinetic and thermodynamic aspects of the relations between the anticancer agent dasatinib and ds-DNA using a pencil lead graphite electrode

The interaction of anticancer drug dasatinib (DSB) with double-stranded calf thymus DNA (ds-DNA) was investigated by using voltammetric techniques on a single-use pencil graphite electrode (PGE). Free DSB displayed a single oxidation peak in acetate buffer solution (pH 4.80). The changes in the anodic CV and DPV peak currents of DSB were investigated in the absence and presence of DNA in aqueous media. Some kinetic parameters, such as diffusion coefficient (D), heterogeneous rate constants (ks), and electrode surface concentration (Γ) of free DSB and DSB-DNA complex, were calculated using CV data. The DSB-DNA complex formation constant (K) and Gibbs free energy (ΔGº) were determined to be 2.51×104 M−1 and 25.10 kJ mol−1, respectively. The results obtained show that there is an interaction between DSB and ds-DNA, and DSB binds to DNA through intercalation interaction. The formation equilibrium constant (K) was found to compare well with similar data reported in the literature. Besides, the thermodynamic parameters (K and ΔGº) obtained by voltammetric measurements were compared with UV spectroscopic data and were found to be approximately of the same order (4.49×104 M−1).

Dasatinib Inhibits Lyn and Fyn Src-Family Kinases in Mast Cells to Suppress Type I Hypersensitivity in Mice.

Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. In vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC50, ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED50, ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

Mechanisms of the Cardiac Myocyte-Damaging Effects of Dasatinib.

The anticancer drug dasatinib (Sprycel) is a BCR-ABL1-targeted tyrosine kinase inhibitor used in treating chronic myelogenous leukemia that has been shown in clinical trials to display cardiovascular toxicities. While dasatinib potently inhibits BCR-ABL1, it is not a highly selective kinase inhibitor and may have off-target effects. A neonatal rat cardiac myocyte model was used to investigate potential mechanisms by which dasatinib damaged myocytes. The anthracycline cardioprotective drug dexrazoxane was shown to be ineffective in preventing dasatinib-induced myocyte damage. Dasatinib treatment increased doxorubicin accumulation in myocytes and doxorubicin-induced myocyte damage, likely through its ability to bind to one or more ABC-type efflux transporters. Dasatinib induced myocyte damage either after a brief treatment that mimicked the clinical situation, or more potently after continuous treatment. Dasatinib slightly induced apoptosis in myocytes as evidenced by increases in caspase-3/7 activity. Dasatinib treatment reduced pERK levels in myocytes most likely through inhibition of RAF, which dasatinib strongly inhibits. Thus, inhibition of the RAF/MEK/ERK pro-survival pathway in the heart may be, in part, a mechanism by which dasatinib induces cardiovascular toxicity.

Abstract 2085: Treatment of human melanoma cells with dasatinib requires inactivation of both mTOR and MAPK pathways to achieve high cell eradication efficacy

Abstract Advanced stages of melanoma are resilient to therapy and new strategies for the treatment are required. About 60% of melanomas harbor the mutated BRAF oncogene, which activate the MAPK pathway. This BRAF driver mutation can be targeted by a small molecule drug vemurafenib. However, most of patients develop resistance during treatment and even drug addiction is acquired. The nonreceptor SRC tyrosine kinase is highly expressed and deregulated in melanoma and can be efficiently inhibited by the inhibitor dasatinib, an anticancer drug which is already used for the treatment of some tumor types. SRC does not have its own canonical pathway but is capable of activating and augmenting different signaling routes in cancer cells. We found that melanoma tumor cell lines analysed were generally resistant to dasatinib irrespective of BRAF or NRAS mutational status. The exception was the cell line Hbl which was very sensitive even to low dasatinib doses and Hbl cells were completely eradicated by 10 nM of dasatinib in several days. The sensitivity of Hbl to dasatinib was dependent on the drug ability to inhibit completely both the MAPK and AKT/mTOR signaling pathways. Dasatinib was capable of inhibiting SRC activation resulting in the repression of AKT activation in Hbl cells. AKT phosphorylation at Ser473 was fully abolished and Thr308 was severely attenuated through inhibiting SRC by dasatinib in Hbl cells. These two phosphorylations are required for AKT activity. MAPK pathway (ERK1/2 phosphorylation) was also inhibited in Hbl cells. Dasatinib also inhibited the phosphorylation of SRC at Tyr416 (a hallmark of SRC activity) in Hbl cells and, surprisingly, also in other dasatinib-resistant melanoma cells. Importantly, although SRC was dephosphorylated at Tyr416, dasatinib was unable to inactivate AKT and MAPK pathway (ERK1/2) in all other melanoma cells. Molecular changes closely correlated with proliferation assays. Our data indicate that the combination therapy of melanoma with dasatinib would bring benefit to patients only by blocking both MAPK and AKT signaling pathways in melanoma cells. Altogether, more molecular knowledge of the effects of the powerful anticancer drug dasatinib is required in order to be used for the treatment of melanoma. This work was supported by the Institutional research project PROGRESQ25 from Charles University Prague. Citation Format: Jiri Vachtenheim, Jiri Réda, Kateřina Vlčková, Lubica Ondrušová. Treatment of human melanoma cells with dasatinib requires inactivation of both mTOR and MAPK pathways to achieve high cell eradication efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2085.

Myristoylation of Src kinase mediates Src-induced and high-fat diet–accelerated prostate tumor progression in mice

Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression.

Redox mechanism, spectrophotometrical characterisation and voltammetric determination in serum samples of kinases inhibitor and anticancer drug dasatinib

The electrochemical oxidation mechanism of the anticancer drug and kinases inhibitor dasatinib was studied by cyclic, differential pulse and square wave voltammetry using a glassy carbon electrode. Dasatinib undergoes irreversible, pH-dependent oxidation in a cascade mechanism. For electrolyte with pH<9.0 two peaks corresponding to consecutive charge transfer reactions that involve the transfer of the same number of electrons and protons were observed. For electrolytes with pH>9.0 only one oxidation peak was observed. The UV–Vis spectra of dasatinib were recorded as a function of pH. The thiazole moiety was identified as the electroactive centre through comparative studies with compounds with similar structures and an oxidation mechanism of dasatinib was proposed. The analytical determination of dasatinib was carried out by differential pulse voltammetry in buffer and serum samples. Adequate recovery results in spiked serum samples were obtained and the matrix effect, serum dilution and dasatinib concentration were evaluated.

Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Protein

Computer simulations are used to determine the free energy landscape for the binding of the anti-cancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published very long time simulations of the ligand binding kinetics for this system [D. E. Shaw et al., J. Am. Chem. Soc. 2011, 133, 9181-9183]

Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase.

Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published microsecond time-scale simulations of the ligand binding kinetics for this system [Shaw, D. E. et al. J. Am. Chem. Soc.2011, 133, 9181−918321545110].

Abstract 5487: The requirements for dasatinib sensitivity in human melanoma cell lines

Abstract Mutated BRAF oncogene, which fuels unregulated MAPK pathway in most melanomas, can be targeted by a small-molecule drug vemurafenib. However, most of patients develop an acquired resistance during treatment or have an intrinsic resistance to this drug. Nonreceptor SRC tyrosine kinase is deregulated in most cancer cell types and can be efficiently inhibited by a small-molecule inhibitor dasatinib, an anticancer drug which is already used for the treatment of some cancers and is in final clinical trials for other tumor types. Although SRC does not have its own canonical pathway, it is capable of activating and augmenting different signaling routes in cancer cells. We found that melanoma tumor cell lines analysed up to date are generally resistant to dasatinib. The exception to this rule was Hbl, a very sensitive cell line whose cells were completely killed by a 10 nM of dasatinib in a few days. The difference in resistance of melanoma cell lines to dasatinib did not depend on primary versus metastatic cell origin or the presence of BRAF or NRAS mutations. Instead, the dasatinib sensitivity was dependent on its ability to inhibit completely both the MAPK and AKT/mTOR signaling pathways. This inhibition was at least as prominent as the inhibition by specific inhibitors of the two pathways. SRC has been reported previously to have links to this signaling pathways with the capacity to inhibit them in some cell types. Moreover, extensive cross-talk exists between the two pathways. Similar results were observed in several other cell lines derived mostly from lung and colorectal cancers. Our data indicate that the singular therapy of melanoma by dasatinib only would bring no benefit to patients, except for the cases (probably rare) where dasatinib strongly blocks both MAPK and AKT signaling pathways in tumor cells. More molecular knowledge about the effects of the powerful anticancer drug dasatinib is required in order to be used for the treatment of melanoma. This work was supported by grant IGA no. NT/14005-3 from the Ministry of Health (Czech Rep.) and by Institutional research project PRVOUK-P25/LF1/2. Citation Format: Jiri Vachtenheim, Jiri Réda, Lubica Ondrušová, Petra Zakova. The requirements for dasatinib sensitivity in human melanoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2014-5487

Influence of microporosity in SBA-15 on the release properties of anticancer drug dasatinib.

The release of the hydrophobic cancer drug dasatinib from two mesoporous silica materials as drug delivery vehicles has been studied. One material is a reference 2D-hexagonal SBA-15 with the typical bimodal pore system with ordered primary mesopores and disordered intrawall pores. The other material is a modified version of the same material where the intrawall porosity in the micropore regime has been selectively removed. Material characterization shows that, with the exception of the difference in intrawall porosity, the materials have identical properties. The drug dasatinib, a tyrosine kinase inhibitor, has been loaded, to the same extent, into the pores of both materials. The two materials give rise to very different release profiles of the drug. The presence of micropores leads to desired release properties: a high initial release of the drug, which is maintained over time. The lack of micropores also leads to a high initial release but followed by a rapid drop in the concentration of released drug, a consequence of its low solubility and hence crystallisation. We suggest that the presence of micropores in the carrier material, and the resultant kinetic release profile, leads to a stabilization of dasatinib in solution and to a sustained supersaturated level of the released drug. Our findings suggest that by controlling the mesoporous host with small variation in the textural properties, the kinetic release and crystallization behaviour of a drug can be altered. It is thus potentially possible to influence the drug post-release and thereby its bioavailability.

Multilayered Polymer-Coated Carbon Nanotubes To Deliver Dasatinib

Multilayered, multifunctional polymer coatings were grafted onto carbon nanotubes (CNTs) using a one-pot, ring-opening polymerization in order to control the release kinetic and therapeutic efficacy of dasatinib. Biocompatible, biodegradable multilayered coatings composed of poly(glycolide) (PGA) and poly(lactide) (PLA) were polymerized directly onto hydroxyl-functionalized CNT surfaces. Sequential addition of monomers into the reaction vessel enabled multilayered coatings of PLA-PGA or PGA-PLA. Poly(ethylene glycol) capped the polymer chain ends, resulting in a multifunctional amphiphilic coating. Multilayer polymer coatings on CNTs enabled control of the anticancer drug dasatinib's release kinetics and enhanced the in vitro therapeutic efficacy against U-87 glioblastoma compared to monolayer polymer coatings.

A new and efficient preparation of 2-aminothiazole-5-carbamides: applications to the synthesis of the anti-cancer drug dasatinib

A new and efficient preparation of 2-aminothiazole-5-carbamides: applications to the synthesis of the anti-cancer drug dasatinib

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

AbstractDasatinib is an oral potent adenosine triphosphate (ATP)–competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcγRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by FcγRIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.