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BMS 354825 hydrochloride

Product NameBMS 354825 hydrochloride
CAS854001-07-3
MFC22H27Cl2N7O2S
MW524.47
EINECS
MOL File854001-07-3.mol

Chemical Properties

Melting point	279-280 °C
storage temp.	under inert gas (nitrogen or Argon) at 2-8°C
solubility	DMSO : 15 mg/mL (28.60 mM; Need ultrasonic and warming)H2O : 10 mg/mL (19.07 mM; Need ultrasonic)
form	Powder
color	White to off-white

Usage And Synthesis

Uses

Dasatinib (BMS-354825) hydrochloride is a highly potent, ATP competitive, orally active dual Src/Bcr-Abl inhibitor with potent antitumor activity. The Kis are 16 pM and 30 pM for Src and Bcr-Abl, respectively. Dasatinib hydrochloride inhibits Bcr-Abl and Src with IC50s of <1.0 nM and 0.5 nM, respectively[1]. Dasatinib hydrochloride also induces apoptosis and autophagy.

in vivo

Dasatinib (5 mg/kg and 50 mg/kg, qd×10d, 5 on-2 off) possesses potent antitumor activity and a high safety margin in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels^[1].
Dasatinib (10 mg/kg) has a pharmacokinetic profile appropriate for continued advancement into in vivo efficacy studies. Dasatinib (10 mg/kg) demonstrates favorable half-lives (t_1/2s) of 3.3 and 3.1 h for i.v. and oral, respectively. The oral bioavailability (F_po) in this study is 27%^[1].

Animal Model:	Nude mice bearing K562 xenografts
Dosage:	5 mg/kg and 50 mg/kg
Administration:	Oral administration on a 5 day on and 2 day off schedule.
Result:	Showed partial tumor regressions after one treatment cycle and complete disappearance of the tumor mass by the end of drug treatment. No toxicity (animal deaths, lack of weight gain) was observed.

Animal Model:	Sprague-Dawley Rats
Dosage:	10 mg/kg (Pharmacokinetic Analysis)
Administration:	Oral and i.v.
Result:	C_max of 13.2 and 0.5 μM for i.v. and oral, respectively.

IC 50

Bcr-Abl: 1.0 nM (IC₅₀); Src: 0.5 nM (IC₅₀); lck: 0.4 nM (IC₅₀); Yes: 0.5 nM (IC₅₀); c-kit: 5.0 nM (IC₅₀); PDGFRβ: 28 nM (IC₅₀); p38: 100 nM (IC₅₀); Her1: 180 nM (IC₅₀); Her2: 710 nM (IC₅₀); FGFR-1: 880 nM (IC₅₀); MEK: 1700 nM (IC₅₀)

References

[1] Lombardo LJ, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004 Dec 30;47(27):6658-61. DOI:10.1021/jm049486a

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