Dacomitinib (PF299804)

Bezeichnung:Dacomitinib (PF299804)

CAS-Nr1110813-31-4

Englisch Name:Dacomitinib (PF299804)

CBNumberCB22566418

SummenformelC24H25ClFN5O2

Molgewicht469.94

MOL-Datei1110813-31-4.mol

Dacomitinib (PF299804) physikalisch-chemischer Eigenschaften

Schmelzpunkt	184-187°C
Siedepunkt	665.7±55.0 °C(Predicted)
Dichte	1.344
storage temp.	Refrigerator
Löslichkeit	DMSO (Slightly), Methanol (Slightly, Heated)
Aggregatzustand	White solid.
pka	12.05±0.43(Predicted)
Farbe	White to Pale Yellow
InChIKey	LVXJQMNHJWSHET-AATRIKPKSA-N
SMILES	C(NC1C(OC)=CC2C(C=1)=C(NC1=CC=C(F)C(Cl)=C1)N=CN=2)(=O)/C=C/CN1CCCCC1
CAS Datenbank	1110813-31-4

Sicherheit

HS Code

29335990

Gefahreninformationscode (GHS)

Dacomitinib (PF299804) Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
The epidermal growth factor receptors (EGFR), whose members include ErbB1 (HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4), are receptor tyrosine kinases that are often over-expressed in cancer. PF-299804 is a second generation pan-ErbB receptor tyrosine kinase inhibitor (IC₅₀s = 6, 45.7, and 73.7 nM for ErbB1, ErbB2, and ErbB4, respectively) that irreversibly binds to the ATP site in the catalytic domains of ErbB receptors. At 15 mg/kg, it demonstrates antitumor activity ranging from delay in tumor growth to complete regression in various tumor xenograft models expressing either wild-type ErbB or mutant ErbB family members that show resistance to first generation ErbB kinase inhibitors.
Verwenden
Dacomitinib is an Erb-inhibitor, or an inhibitor of the members of the epidermal growth factor receptor family. Used as an ant-cancer agent due to observation of over-expressed epidermal growth factor receptor in nearly all cases of squamous cell carcinoma in the head and neck.
Verwenden
PF299804 is a potent, irreversible pan-ErbB inhibitor against ErbB1, ErbB2 and ErbB4 with IC50 of 6 nM, 45.7 nM and 73.7 nM, respectively.
Definition
ChEBI: A member of the class of quinazolines that is 7-methoxyquinazoline-4,6-diamine in which the amino group at position 4 is substituted by a 3-chloro-4-fluorophenyl group and the amino group at position 6 is substituted by an (E)-4-(piperidin 1-yl)but-2-enoyl group.
Trademarks
Vizimpro^TM
Allgemeine Beschreibung
Class: receptor tyrosine kinase
Treatment: NSCLC with EGFR alterations
Oral bioavailability = 80%
Elimination half-life = 70 h
Protein binding = 98%
in vitro
dacomitinib reduced the phosphorylation of her2, egfr, her4, akt, anderkin the majority of sensitive lines. dacomitinib exerted its antiproliferative effect through a combined g0–g1 arrest and an induction of apoptosis. dacomitinib inhibited growth in several her2-amplified lines with de novo and acquired resistance to trastuzumab. dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. this study identifies her2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in her2-amplified breast cancers resistant to trastuzumab and lapatinib [1].
in vivo
to evaluate the in vivo efficacy of pf00299804, the authors generated xenografts in nu/nu mice using hcc827 gfp and hcc827 del/t790m cells and treated the mice with pf00299804. pf00299804 effectively inhibited the growth of hcc827 gfp xenografts. pf00299804 treatment was substantially more effective at inhibiting growth of this xenograft model than gefinitib. thus, these preclinical models suggest that pf00299804 may be quite effective against lung cancers that become resistant to gefitinib or erlotinib via acquisition of a t790m mutation in egfr [2].
target
ErbB1
IC 50
6 nm (egfr); 45.7 nm (erbb2); 73.7 nm (erbb4)
Lager
Store at +4°C
Einzelnachweise
[1] kalous o, conklin d, desai aj, o'brien na, ginther c, anderson l, cohen dj, britten cd, taylor i, christensen jg, slamon dj, finn rs. dacomitinib (pf-00299804), an irreversible pan-her inhibitor, inhibits proliferation of her2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib. mol cancer ther. 2012;11(9):1978-87.
[2] engelman ja, zejnullahu k, gale cm, lifshits e, gonzales aj, shimamura t, zhao f, vincent pw, naumov gn, bradner je, althaus iw, gandhi l, shapiro gi, nelson jm, heymach jv, meyerson m, wong kk, jfinne pa. pf00299804, an irreversible pan-erbb inhibitor, is effective in lung cancer models with egfr and erbb2 mutations that are resistant to gefitinib. cancer res. 2007;67(24):11924-32.

Dacomitinib (PF299804) Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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