| Identification | Back Directory | [Name]
Dacomitinib (PF299804) | [CAS]
1110813-31-4 | [Synonyms]
PF299
PF299804
Dacomitinib
PF-00299804
PF-00299804-03
Dacomitinib, >=98%
DacoMitinib,PF299804
DacoMitinib (PF-00299804)
DacoMitinib (PF299804, PF299)
dacomitinib (pan-HER inhibitor)
DacoMitinib (PF299804,PF-00299804)
(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide
(E)-N-(4-((3-chloro-4-fluorophenyl)aMino)-7-Methoxyquizolin-6-yl)-4-(piperidin-1-yl)but-2-eMide
(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
2-Butenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-, (2E)-
(2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide Dacomitinib (PF299804, PF299) | [EINECS(EC#)]
-0 | [Molecular Formula]
C24H25ClFN5O2 | [MDL Number]
MFCD19443734 | [MOL File]
1110813-31-4.mol | [Molecular Weight]
469.939 |
| Chemical Properties | Back Directory | [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 | [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 DataBase Reference]
1110813-31-4 |
| Hazard Information | Back Directory | [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. | [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 -20°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. |
| Questions And Answer | Back Directory | [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). |
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