Description Biological activity Uses Binding Mode Clinical Study
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Dacomitinib (PF299804)

Description Biological activity Uses Binding Mode Clinical Study
Product Name
Dacomitinib (PF299804)
CAS No.
1110813-31-4
Chemical Name
Dacomitinib (PF299804)
Synonyms
Dacomitinib;PF299804;(E)-N-(4-((3-chloro-4-fluorophenyl)aMino)-7-Methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enaMide;(2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide Dacomitinib (PF299804, PF299);PF299;CS-168;Dachtini;Dakotinib;dacatinib;PF-00299804
CBNumber
CB22566418
Molecular Formula
C24H25ClFN5O2
Formula Weight
469.94
MOL File
1110813-31-4.mol
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Dacomitinib (PF299804) Property

Melting point:
184-187°C
Boiling point:
665.7±55.0 °C(Predicted)
Density 
1.344
storage temp. 
Refrigerator
solubility 
DMSO (Slightly), Methanol (Slightly, Heated)
form 
White solid.
pka
12.05±0.43(Predicted)
color 
White to Pale Yellow
CAS DataBase Reference
1110813-31-4
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Safety

HS Code 
29335990
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H302Harmful if swallowed

Precautionary statements

P280Wear protective gloves/protective clothing/eye protection/face protection.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

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N-Bromosuccinimide Price

TCI Chemical
Product number
D5450
Product name
Dacomitinib
Purity
>98.0%(HPLC)
Packaging
50mg
Price
$145
Updated
2023/06/20
TCI Chemical
Product number
D5450
Product name
Dacomitinib
Purity
>98.0%(HPLC)
Packaging
250mg
Price
$494
Updated
2023/06/20
Cayman Chemical
Product number
9001879
Product name
PF-299804
Purity
≥98%
Packaging
1mg
Price
$44
Updated
2024/03/01
Cayman Chemical
Product number
9001879
Product name
PF-299804
Purity
≥98%
Packaging
5mg
Price
$193
Updated
2024/03/01
Cayman Chemical
Product number
9001879
Product name
PF-299804
Purity
≥98%
Packaging
10mg
Price
$341
Updated
2024/03/01
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Dacomitinib (PF299804) Chemical Properties,Usage,Production

Description

Dacomitinib is a selective and irreversible inhibitor of EGFR. It is a drug candidate for the treatment of non-small cell lung carcinoma. It is current under the Phase III clinical trials. It also shows potential for the treatment of HER-2 amplified breast cancer cells lines that are resistant to trastuzumab and lapatinib. 

Biological activity

Dacomitibib (Dacomitinib, PF299804) is an effective and irreversible pan-ErbB inhibitor that is most effective in EGFR, with an IC50 of 6 nM. It is also highly effective in NSCLCs that carries EGFR or ERBB2 mutants (against Gefitinib) and EGFR T790M mutant. Phase 2.
Dacomitinib is taken orally once-daily. It is an irreversible inhibitor of HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases. Dacomitinib targets multiple receptors of the HER pathway, whereas currently marketed HER-1 (EGFR) inhibitors for non-small cell lung cancer (NSCLC) target only one receptor in this pathway,developed by Pfizer.

Uses

Dacomitinib (PF299804), which name is (E)-N-[4-(3-chloro-4-fluoroanilino)-7- methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide, is a potent, orally available, highly selective, irreversible small-molecule tyrosine kinase inhibitor (TKI) of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. It is most effective against EGFR with IC50 of 6 nM. It is highly effective against NSCLCs carrying EGFR or ERBB2 mutant (anti-Gefitinib) and EGFR T790M mutant.

Binding Mode

In the crystal structure of dacomitinib in complex with the EGFR gatekeeper T790M mutant, the kinase adopts an inactive conformation, with the αC helix displaced. The quinazoline ring occupies the ATP-binding site, with the ring nitrogen forming a single hydrogen bond with the amide NH of Met793 in the hinge. The fluorochloroaniline group approaches the deep end of the ATP-binding pocket, making favorable interactions with a hydrophobic cluster in the region. The aniline nitrogen interacts indirectly with Asn842 and Asp855 via bound water molecules. Most importantly, the inhibitor forms the expected covalent bond with Cys797 at the edge of the active site cleft and the butenamide Michael-acceptor group, making binding irreversible.

Clinical Study

Dacomitinib has advanced to several Phase III clinical trials. The results of the first trials were disappointing, with a failure to meet the study goals, Additional Phase III trials are ongoing.
Clinical evaluation of dacomitinib is ongoing in a number of clinical trials in patients with advanced NSCLC across lines of therapies and a range of histologies and molecular subtypes, such as EGFR and KRAS status.
Additionally, there is an ongoing clinical trial evaluating dacomitinib in recurrent and/or metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN).

Description

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.

Uses

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.

Uses

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.

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.

brand name

VizimproTM

General Description

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)

storage

Store at +4°C

References

[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) Preparation Products And Raw materials

Raw materials

Preparation Products

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Dacomitinib (PF299804) Suppliers

WuHu Linze pharmaceutical Co.,Ltd.
Tel
0553-0553-5802116 18356571950
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2592492800@qq.com
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China
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Wuhan Bo Jin Biotechnology Co.,Ltd.
Tel
18164232327
Email
2709603029@qq.com
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China
ProdList
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Shanghai Boyle Chemical Co., Ltd.
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Fax
86-21-57758967
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sales@boylechem.com
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China
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Chembest Research Laboratories Limited
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+86-21-20908456
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021-58180499
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sales@BioChemBest.com
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China
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TCI (Shanghai) Development Co., Ltd.
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021-67121386
Fax
021-67121385
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Sales-CN@TCIchemicals.com
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China
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24529
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JinYan Chemicals(ShangHai) Co.,Ltd.
Tel
13817811078
Fax
86-021-50426522,50426273
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sales@jingyan-chemical.com
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China
ProdList
9976
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Adamas Reagent, Ltd.
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400-6009262 16621234537
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021-64823266
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chenyj@titansci.com
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China
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Jinan Trio PharmaTech Co., Ltd.
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+86 (531) 88811783
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+86 (531) 55696010 QQ 1762738062
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sales@trio-pharmatech.com (International market)
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China
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Dalian Meilun Biotech Co., Ltd.
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0411-62910999 13889544652
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meilunui@163.com
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China
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Shanghai Xiannuo Biotechnology Co., Ltd.
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021-50718719 13918719472
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021-50718719
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China
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979
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View Lastest Price from Dacomitinib (PF299804) manufacturers

Nanjing Fred Technology Co., Ltd
Product
Dacomitinib 1110813-31-4
Price
US $0.00-0.00/kg
Min. Order
1kg
Purity
99%,single impurity<0.1
Supply Ability
1 ton
Release date
2023-12-22
WUHAN FORTUNA CHEMICAL CO., LTD
Product
Dacomitinib 1110813-31-4
Price
US $0.00/g
Min. Order
100g
Purity
99%min
Supply Ability
1000g
Release date
2021-11-16
Hebei Yanxi Chemical Co., Ltd.
Product
Dacomitinib (PF299804) 1110813-31-4
Price
US $0.00/kg
Min. Order
1kg
Purity
0.99
Supply Ability
20tons
Release date
2023-10-09

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