302962-49-8

Hazard Information

Questions And Answer

• Leukemia drug

  Dasatinib is an oral potent oncogenic kinase inhibitor, which can block signal of cancer cell replication acceleration , in May 2009, the US Food and Drug Administration (FDA) formally approved the sale of dasatinib , It has been clinically used for the treatment of various chronic myeloid leukemia (CML), including treatment of chronic myeloid leukemia which is resistant or intolerant to the treating programs including imatinib mesylate., Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) and the treatment of patients with solid tumors.
  
  October 28, 2010 ,the FDA approved dasatinib (Sprycel) of the new indication which is used for the treatment of the rare leukemia first diagnosed Philadelphia chromosome-positive called chronic myeloid leukemia (Ph + CP-CML) . The disease is a blood and bone marrow disease associated with genetic abnormality .
  An open-label randomized clinical trial conducted in patients with CP-CML evaluated the  safety and efficacy of dasatinib . Common side effects include decreased activity of the bone marrow caused by red blood cells, white blood cells and platelets decreased (myelosuppression), fluid retention, diarrhea, headache, musculoskeletal pain, and rash.
  October 11, 2011, the US Food and Drug Administration (FDA) said the leukemia drug dasatinib (Sprycel, Bristol-Myers Squibb Company) might increase pulmonary arterial hypertension (PAH) risk. Pulmonary hypertension is a rare but serious disease that can lead to the condition that heart pumping blood to the lungs becomes more difficult by raising the pressure . PAH symptoms include shortness of breath, fatigue, swelling of the legs and ankles, clinicians must differentiate these symptoms  from other similar symptoms.
  Since 2006 Dasatinib was approved in the US market ,there had been  12 associated pulmonary hypertension events  ,pulmonary hypertension symptoms included shortness of breath, fatigue, hypoxia and fluid retention, patients then were confirmed pulmonary hypertension by the results of right heart catheterization ,studies have shown that the biggest cause of the disease may come from patients taking dasatinib.
  The above information is edited by the Chemicalbook of Tian Ye.;

• Chemical properties

  Dasatinib is a white to off-white powder and has a melting point of 280°-286° C. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL™ (dasatinib) is an inhibitor of multiple tyrosine kinases.SPRYCEL tablets are white to offwhite, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.
  https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021986lbl.pdf;

• Mechanism of Action

  Dasatinib (former BMS 354825), or N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2- hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carbox- amide monohydrate (C22H26ClN7O2S), is an orally available small-molecule multitargeted kinase inhibitor. Dasatinib was discovered by and named after Jagabandhu Das (Lombardo et al. 2004; Das et al. 2006) as part of an effort to develop potent inhibitors of SRC family kinases (SFKs).
  The compound targets the SRC family of kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK). In addition, and clinically more significant, da- satinib inhibits BCR-ABL with greater potency compared to other BCR-ABL inhibitors.
  
  It also inhibits receptor tyrosine kinases (c-KIT, PDGFR, DDR1 and 2, c-FMS, ephrin receptors) and TEC family kinases (TEC and BTK) (Table 1).
  Preclinical studies suggest that dasatinib induces apoptosis in only a small subset of cell lines. Inhibition of migration, invasion, and cell adhesion by da- satinib is reported more frequently (Johnson et al. 2005; Nam et al. 2005; Serrels et al. 2006). It has been demonstrated that dasatinib induces defects in spindle generation, cell cycle arrest, and centrosome alterations in leukemic cells, tumor cell lines, and also in normal cells. These effects are not attributable to the inhi- bition of a single kinase; rather it is expression of nonspecific effects on multiple kinases (Fabarius et al. 2008).
  In a nude mouse model of prostate cancer, tumor growth and the development of lymph node metastasis were inhibited by dasatinib (Park et al. 2008). In addition, Dasatinib acts also on the tumoral microenvironment, especially in bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect (Metcalf et al. 2002).;

• Pharmacokinetics

  Dasatinib is administered orally. The drug is rapidly absorbed, peak plasma concentrations occur 0.5-3 h after administration. The intake of food is not relevant for pharmacokinetics of dasatinib. In a dose range of 25-120 mg twice daily, the area under the plasma concentration—time curve (AUC) increased proportionally. The drug is extensively metabolized in the liver, predominantly by cytochrome P 450 (CYP) 3A4, only 30 % remain unchanged. The metabolites of the compound are unlikely to play a pharmacologic role. There were linear elimination characteristics over the above-mentioned dose range with a terminal elimination half-life of 5-6 h.
  Elimination occurs mostly in the feces (85 %) only little in urine (4 %). Dasatinib is excreted as metabolites, only 19% of a dose was recovered as unchanged drug in the feces (SprycelÒBMS 2012).;

• Uses

  Dasatinib is a novel, potent,  and multi-targeted inhibitor that targets Abl, Src and c-Kit, with IC50 of ＜1 nM, 0.8 nM and 79 nM, respectively. It could directly targets wild-type and mutant c-Abl kinase domains. As a small-molecule Tyrosine Kinase Inhibitor (TKI) for the treatment of CML, dasatinib is used to treat a certain type of chronic myeloid leukemia (CML; a type of cancer of the white blood cells) as a first treatment and in people who can no longer benefit from other leukemia medications including imatinib (Gleevec) or in those who cannot take these medications because of side effects. It is also used to treat a certain type of chronic CML in children. Dasatinib could used to treat a certain type of acute lymphoblastic leukemia (ALL; a type of cancer of the white blood cells) in people who can no longer benefit from other leukemia medications or who cannot take these medications because of side effects. Dasatinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.
  https://medlineplus.gov/druginfo/meds/a607063.html;

• Drug Interactions

  Dasatinib is a substrate and an inhibitor of CYP3A4. Therefore, there is a potential for interaction with other concomitantly administered drugs that are metabolized primarily by or modulate the activity of CYP3A4.
  Systemic exposure to dasatinib is increased if it is coadministered with drugs that are inhibitors of CYP 3A4 (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole).
  If coadministered with drugs that induce CYP 3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John’s Wort), dasatinib AUC is reduced. It was reduced by 82% when coadministered with rifampicin.
  Dasatinib AUC was reduced when coadministered with H2-blockers/protonpump inhibitors, or antacids. Concomitant administration of famotidin reduced dasatinib AUC by 61%, coadministration of aluminum hydroxide by 55%.
  Dasatinib is an inhibitor of CYP3A4. Substrates of CYP3A4 with a narrow therapeutic index should be administered with caution in patients receiving dasatinib. Drugs that rank among that list are alfentanil, astemizole, terfenadine, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloid (ergotamine, dihydroergotamine) (SprycelÒBMS 2012).;

• Toxicology

  Dasatinib has a unique safety profile and since early clinical trials some AEs have been consistently reported in patients receiving dasatinib including myelosup- pression, fluid retention, pleural effusion, gastrointestinal disorders, fatigue, headache, musculoskeletal disorders, rash, and infection (Table 8). Some bleeding events have also been reported. More recently, cases of pulmonary arterial hypertension (PAH), a subcategory of pulmonary hypertension (PH), have been reported in a small number of patients receiving dasatinib (Galie et al. 2009; McLaughlin et al. 2009; Fang et al. 2012). In clinical trials of first-line and second- line dasatinib, most AEs occurred within 12—24 months of treatment and were managed with dose modifications (Kantarjian et al. 2012; Shah et al. 2012; SprycelÒBMS 2012).
  Small Molecules in Oncology;

• Binding Mode

  In the co-crystal structures of the two molecules of dasatinib (green and blue) in the asymmetric unit cell with ABL, it binds to an active DFG-information of ABL. The aminothiazole core, which is orthogonal to the 2-chloro-6-methylphenyl moiety, occupies the site that normally binds the adenine group of ATP. The pyrimidine NH and the thiazole nitrogen interact with the backbone amide carbonyl and NH of the hinge region Met318, and the carboxamide NH forms an H-bond with the side chain hydroxyl of Thr315. The terminal hydroxyethyl group interacts differently with each of the two molecules in the asymmetric unit cell: (1) via a hydrogen bond between the hydroxyethyl group and the backbone carbonyl of Tyr320; and (2) with the hydroxyethyl group pointing in the opposite direction and approaching the solvent front. By binding strongly to the active conformation of ABL within the ATP-binding site (vs. the inactive conformation for imatinib), dasatinib efficiently competes with ATP. Due to a different binding mode from that of imatinib, it maintains cellular activity against most imatinib-resistant BCR-ABL mutations (but not the T315I mutation due to the loss of a hydrogen bond with T315 and increased steric clash with the bulky isobutyl chain of 315I). Unfortunately, binding to the more highly conserved active conformation results in reduced selectivity relative to imatinib, and as a result, dasatinib inhibits many additional protein kinases at physiologically relevant concentrations.
  ;

Spectrum Detail

Supplier

Related Products