Tozasertib Chemical Properties

Melting point:

248-253°C (dec.)

Density 

1.40±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

Soluble in DMSO (up to 100 mg/ml).

form 

powder

pka

14.09±0.70(Predicted)

color 

white to beige

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.

Tozasertib Usage And Synthesis

Description

The Aurora kinases (A, B, and C) are a family of serine-threonine kinases that regulate various stages of mitotic function. With significant roles in cell cycle and cell division, Aurora kinase gene amplification and overexpression are linked to tumorigenesis. MK-0457 is a potent pan-Aurora kinase inhibitor but favors Aurora A (K_i = 0.6 nM) over Aurora B (K_i = 18 nM) or Aurora C (K_i = 4.6 nM). It shows selectivity against a panel of more than 190 different protein kinases. MK-0457 effectively inhibits proliferation of several different cell lines of clear cell renal carcinoma (IC₅₀s = <10 μM) and blocks the growth of tumors in a rodent model of cancer (80 mg/kg), inhibiting histone H3 phosphorylation and increasing apoptosis. By depleting Aurora activity, MK-0457 disrupts bipolar spindle formation during mitosis, arresting cell cycle progression at the G₂/M phase.

Chemical Properties

White Solid

Uses

Tozasertib is used as a multikinase inhibitor once used for cancer treatment.

Definition

ChEBI: N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide is a N-arylpiperazine.

Biochem/physiol Actions

VX-680 is an ATP site-targeting potent aurora kinase inhibitor (Aurara A/B/C Ki(app) = 0.6/18/4.6 nM) that affects FLT3, BCR-Abl, BCR-Abl (T315I), Lck, ITK, Src, and Fyn only at higher concentrations (Ki(app) = 30, 30, 42, 80, 220, 350, 520 nM, respectively) and exhibits little inhibitory potency toward 52 other kinases (Ki(app) >1 μM). VX-680 exhibits potent antiproliferation activity in a wide variety of cancer cultures (IC50 from 15 to 113 nM) as a result of cell cycle arrest and apoptosis induction, as well as causes tumor retardation (by 98% on day 13; 75 mg/kg b.i.d i.p.; HL-60 in mice) and regression (2 mg/kg/h 3 d/wk i.v. infusion; HCT116 in rats) in vivo. Crystallography data reveal a tight association of VX-680 with a hydrophobic pocket present only in a closed, inactive kinase conformation, which forms the basis of its selectivity profile, including its activity toward wild-type and the Imatinib-resistant (T315I) Abl.

Synthesis

General synthesis of N-(4-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl)sulfanyl)phenyl)aminocyclopropanecarboxylic acid) and N-[4-[[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)pyrimidin-2-yl]sulfanyl]phenyl]aminocyclopropane carboxylic acid as the raw materials The procedure was as follows: N-methylpiperazine (10 mL) was added to compound D (2.373 g, 5.92 mmol) and the reaction mixture was stirred at 110°C for 2 hours. Upon completion of the reaction, the excess N-methylpiperazine was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium bicarbonate and dried over magnesium sulfate, and subsequently concentrated. The resulting residue was purified by methanol crystallization to afford colorless crystals of target product I (1.82 g, 66% yield). The product was characterized by 1H-NMR (DMSO-d6) with chemical shifts δ of 0.81 (4H, d), 1.79 (1H, m), 2.01 (3H, s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.42 (1H, s), 6.02 (1H, br s), 7.47 (2H, d), and 7.69 (2H, d), 9.22 (1H, s), 10.39 (1H, s), 11.69 (1H, s).

References

[1] ELIZABETH A HARRINGTON. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo[J]. Nature Medicine, 2004, 10 3: 262-267. DOI:10.1038/nm1003
[2] FEI FEI. Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias.[J]. Molecular Cancer Therapeutics, 2010: 1318-1327. DOI:10.1158/1535-7163.mct-10-0069
[3] ALEXANDER DEWERTH. In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma.[J]. Pediatric Surgery International, 2012: 579-589. DOI:10.1007/s00383-012-3086-6

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