1035270-39-3 Usage
Description
AZD-4547 is a novel, selective, and potent inhibitor of fibroblast growth factor receptor (FGFR) tyrosine kinases, specifically targeting FGFR1, 2, and 3 with high affinity. It is a pale yellow solid and is currently in Phase 2/3 of clinical trials. AZD-4547 has demonstrated antiproliferative activity in tumor cell lines expressing deregulated FGFRs and has shown potent dose-dependent antitumor activity in an FGFR-driven human tumor xenograft mouse model.
Uses
Used in Oncology:
AZD-4547 is used as an anticancer agent for the treatment of FGFR-dependent tumors. It is particularly effective in inhibiting FGFR1, 2, and 3 tyrosine kinases, which are often deregulated in various types of cancers. By selectively targeting these FGFRs, AZD-4547 can potentially inhibit tumor growth and progression in patients with FGFR-dependent tumors.
Used in Drug Development:
AZD-4547 serves as a valuable compound in the development of targeted therapies for cancer treatment. Its high selectivity for FGFR1, 2, and 3 makes it an attractive candidate for further research and development in the field of oncology. Additionally, its demonstrated antitumor activity in preclinical models highlights its potential as a therapeutic agent for patients with FGFR-driven cancers.
Used in Clinical Trials:
AZD-4547 is currently being investigated in Phase 2/3 clinical trials to evaluate its safety, efficacy, and optimal dosing regimen for the treatment of FGFR-dependent tumors. These trials aim to determine the potential benefits and risks associated with the use of AZD-4547 in cancer patients and to establish its role in the treatment landscape for FGFR-driven malignancies.
Features
Greater selectivity for FGFR1-3 over FGFR4. AZD4547 is active against the tyrosine kinase activity of both the wild-type and mutant forms of FGFR.
In vitro
Compared to FGFR1-3, AZD4547 displays weaker activity against FGFR4 with IC50 of 165 nM. AZD4547 only inhibits recombinant VEGFR2 (KDR) kinase activity with IC50 of 24 nM, in the in vitro selectivity test against a diverse panel of representative human kinases. AZD4547 at 0.1 μM exhibits no activity against a range of recombinant kinases including ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2, and PI3-kinase. Consistently, the potent selectivity of AZD4547 for FGFR1-3 over FGFR4, IGFR, and KDR is also observed in cellular phosphorylation assays. AZD4547 has potent in vitro antiproliferative activity only against tumor cell lines expressing deregulated FGFRs such as KG1a, Sum52-PE, and KMS11 with IC50 of 18-281 nM, and is inactive against MCF7 as well as more than 100 additional tumor cell lines. AZD4547 treatment potently inhibits FGFR and MAPK phosphorylation in human tumor cell lines in a dose-dependent manner. AZD4547 also potently inhibits the phosphorylation of FRS2 and PLCγ, downstream markers of FGFR signaling. Notably, AZD4547 affects the AKT phosphorylation in the breast cell lines, MCF7 and Sum52-PE but not in KG1a and KMS11 lines. AZD4547 treatment significantly induces apoptosis in Sum52-PE and KMS11 cells, dramatically increases G1 arrest but not apoptosis in KG1a cells, and has no effect on cell cycle distribution or apoptosis in MCF7 cells.
In vivo
Oral administration of AZD4547 at 3 mg/kg twice daily in mice bearing KMS11 tumors results in significant tumor growth inhibition of 53% when compared with vehicle-treated controls, and AZD4547 at 12.5 mg/kg once daily or 6.25 mg/kg twice daily leads to complete tumor stasis, which is associated with dose proportional pharmacodynamic modulation of phospho-FGFR3 and reduced KMS11 tumor cell proliferation. Moreover, oral administration of AZD4547 at 12.5 mg/kg once daily results in 65% tumor growth inhibition in the FGFR1-fusion KG1a xenograft model. At efficacious dose levels, AZD4547 does not exhibit antiangiogenic effects. AZD4547 has no significant effect on blood pressure and therefore lacks in vivo anti-KDR activity. Consistently, dosing of 6.25 mg/kg orally twice daily AZD4547 is inactive in the cediranib-sensitive xenograft models including Calu-6, HCT-15 and LoVo.
Check Digit Verification of cas no
The CAS Registry Mumber 1035270-39-3 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,3,5,2,7 and 0 respectively; the second part has 2 digits, 3 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 1035270-39:
(9*1)+(8*0)+(7*3)+(6*5)+(5*2)+(4*7)+(3*0)+(2*3)+(1*9)=113
113 % 10 = 3
So 1035270-39-3 is a valid CAS Registry Number.
1035270-39-3Relevant articles and documents
New and convergent synthesis of AZD 4547
Bu, Lehao,Chen, Wenxin,Gao, Lei,Mao, Yongjun,Sun, Cong,Wang, Han
, p. 276 - 282 (2020/06/10)
A practical and convergent synthetic route of AZD 4547 was developed successfully. The intermediate 5-(3,5-dimethoxyphenylethyl)-1H-pyrazol-3-amine (7) was prepared from 3,5-dimethoxybenzaldehyde through 6 simple steps in 52.3% yield. Another intermediate 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzoic acid (14) was synthesized from ethyl 4-fluorobenzoate and (2R,6S)-2,6-dimethylpiperazine in 62% yield over 2 steps. Finally, AZD 4547 was obtained from 7 and 14 in 73% yield and 99.1% purity. Purification methods of the intermediates and the final product involved in the route were developed.
NOVEL COMPOUNDS
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Page/Page column 145, (2008/12/06)
There is provided a compound of formula (I): or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula 1, and the use of a compound of Formula 1 as a medicament and in the treatment of cancer.
