1110813-31-4 Usage
Description
Dacomitinib (PF299804), also known as (E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide, is a potent, orally available, highly selective, and irreversible small-molecule tyrosine kinase inhibitor (TKI) that targets the human epidermal growth factor receptors (HER) family, including HER1 (EGFR), HER2, and HER4. It is particularly effective against EGFR with an IC50 of 6 nM and shows significant efficacy against non-small cell lung carcinoma (NSCLC) with EGFR or ERBB2 mutations, as well as EGFR T790M mutations.
Uses
Used in Oncology:
Dacomitinib (PF299804) is used as an ant-cancer agent for the treatment of non-small cell lung carcinoma (NSCLC) due to its effectiveness against EGFR and ERBB2 mutant tumors. It is currently undergoing Phase III clinical trials and has shown potential in treating HER-2 amplified breast cancer cell lines that are resistant to trastuzumab and lapatinib.
Used in Head and Neck Cancer Treatment:
Dacomitinib (PF299804) is used as an ant-cancer agent in the treatment of squamous cell carcinoma in the head and neck, as it targets the over-expressed epidermal growth factor receptor, which is commonly observed in these types of cancers.
Used in Targeted Cancer Therapy:
As a second-generation pan-ErbB receptor tyrosine kinase inhibitor, Dacomitinib (PF299804) is used to inhibit the activity of ErbB1, ErbB2, and ErbB4 receptors, which are often over-expressed in cancer cells. It irreversibly binds to the ATP site in the catalytic domains of ErbB receptors, demonstrating antitumor activity in various tumor xenograft models expressing either wild-type or mutant ErbB family members that show resistance to first-generation ErbB kinase inhibitors.
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.
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).
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].
IC 50
6 nm (egfr); 45.7 nm (erbb2); 73.7 nm (erbb4)
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.
Check Digit Verification of cas no
The CAS Registry Mumber 1110813-31-4 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,1,1,0,8,1 and 3 respectively; the second part has 2 digits, 3 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1110813-31:
(9*1)+(8*1)+(7*1)+(6*0)+(5*8)+(4*1)+(3*3)+(2*3)+(1*1)=84
84 % 10 = 4
So 1110813-31-4 is a valid CAS Registry Number.
InChI:InChI=1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+
1110813-31-4Relevant articles and documents
Preparation method of dacotinib
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Paragraph 0051-0064, (2022/01/10)
The present invention discloses a method of preparation of dacotinib, comprising the following steps: (N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazoline) in a base / methanol system to undergo a methyl oxidation reaction, to compound 02 (N- (3-
Preparation method of Dacomitinib
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, (2021/06/23)
The invention provides a preparation method of Dacomitinib. Specifically, 3-amino-4-methoxybenzonitrile is used as a raw material and is subjected to a condensation reaction with 4-(piperidine-1-yl) butyl-2-enoyl chloride, a product is subjected to nitration and reduction, condensation with DMF-DMA is performed, and cyclization reaction with 3-chloro-4-fluorophenylamine is performed to prepare the Dacomitinib. The preparation method has the advantages of simple and safe synthesis route and operation, easily available raw materials, simple post-treatment and high yield, and is suitable for industrial production.
Preparation method of dacomitinib intermediate
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, (2021/04/28)
The invention provides a preparation method of a dacomitinib intermediate. The preparation method comprises steps shown in the specification. The invention provides the novel preparation method of the dacomitinib key intermediate, the intermediate is short in synthetic route, mild in reaction condition, short in reaction time and simple in separation and purification method, raw materials and reagents are conventional reagents, the cost is low, the yield of the prepared product is high, and the method is very beneficial to industrial production and popularization and has a good application prospect.
