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Cancer Treatment Steroid Powder AZD-4547

Cancer Treatment Steroid Powder AZD-4547

Antineoplastic Agents AZD9291 CAS 1421373-65-0 AZD9291 a third-generation orally irreversible epidermal growth factor receptor (EGFR) inhibitor, is under development by British drug maker AstraZeneca for the treatment of patients with metastatic EGFR T790M mutation-positive non-small cell lung...

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Cancer Treatment Steroid Powder AZD-4547

AZD-4547 Quick details :

AZD-4547;AZD4547, >=98%;AZD4547/AZD-4547;AZD4547, Free Base, >99%;rel-N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide;N-(5-(3,5-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((3R,5S)-rel-3,5-dimethylpiperazin-1-yl)benzamide;rel-N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]benz;rel-N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]benzamide;rel-N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]benzamide AZD4547

AZD4547 also inhibits recombinant VEGFR2 (KDR) kinase activity with an IC50 of 24 nM. In KG1a, Sum52-PE, MCF7, and KMS11 cell lines, AZD4547 potently inhibits autophosphorylation of FGFR1, 2, and 3 tyrosine kinases (IC50 values of 12, 2, and 40 nM, respectively) and displays weaker inhibition of FGFR4 cellular kinase activity (IC50=142 nM). Significantly weaker inhibitory activity is observed versus cellular KDR and IGFR ligand-induced phosphorylation (IC50 values of 258 and 828 nM, respectively), representing approximately 20- and 70-fold selectivity over cellular FGFR1. Besides, AZD4547 potently inhibits FGFR phosphorylation and downstream signaling affected through FRS2, PLCγ, and MAPK at the cellular leve. Female SCID mice bearing KMS11 tumors are randomized and treated chronically with AZD4547 at a range of well-tolerated doses. Oral AZD4547 treatment results in dose-dependent tumor growth inhibition. Twice daily administration of AZD4547 at 3 mg/kg gives statistically significant tumor growth inhibition of 53% (P<0.0005 by one-tailed t test) when compare with vehicle-treated controls, whereas doses of 12.5 mg/kg once daily and 6.25 mg/kg twice daily results in complete tumor stasis (P<0.0001). A further efficacy study in the KG1a model with 12.5 mg/kg once daily AZD4547 results in 65% tumor growth inhibition (P=0.002)

AZD-4547 Biological activity

AZD4547 is a novel and selective FGFR inhibitor targeted at FGFR1/2/3 with an IC50 of 0.2 nM/2.5 nM/1.8 nM and has weak activity on FGFR4 and VEGFR2 (KDR), and on IGFR, CDK2 There is almost no activity with p38. Phase 2/3.

AZD-4547 In vitro studies

Compared with FGFR1-3, AZD4547 acts on FGFR4 with weak activity with an IC50 of 165 nM. AZD4547 only inhibited recombinant VEGFR2 (KDR) kinase activity with an IC50 of 24 nM and selectively acted on a panel of multiple representative human kinases in vitro. 0.1 μM AZD4547 acts on a series of recombinant kinases including ALK, CHK1, EGFR, MAPK1, MEK1, p70S6K, PDGFR, PKB, Src, Tie2, and PI3K with no activity. Correspondingly, in the cell phosphorylation assay, it was observed that the selectivity of AZD4547 on FGFR1-3 was higher than that on FGFR4, IGFR, and KDR. In vitro, AZD4547 only exerts anti-proliferative activity against tumor cells expressing deregulated FGFRs such as KG1a, Sum52-PE, and KMS11, with IC50 of 18-281 nM, but no activity against MCF7 and more than 100 other tumor cells. AZD4547 treats human tumor cells and effectively inhibits FGFR and MAPK phosphorylation in a dose-dependent manner. AZD4547 also effectively inhibits FRS2 and PLCγ phosphorylation, as well as downstream FGFR signaling. In addition, AZD4547 affects the AKT phosphorylation in breast cell lines MCF7 and Sum52-PE but not KG1a and KMS11 cells. AZD4547 treatment of Sum52-PE and KMS11 cells significantly induced apoptosis, acting on KG1a cells, significantly increased cell cycle arrest in G1 phase rather than apoptosis, and on MCF7 cells, had no effect on cell cycle distribution and apoptosis.

AZD-4547 In vivo studies

AZD4547 was orally administered to mice bearing KMS11 tumors at a dose of 3 mg/kg, twice daily, and significantly inhibited 53% of tumor growth compared to the control group. AZD4547 was treated once daily at 12.5 mg/kg, or 6.25 mg/day. Dosing twice daily with a kg dose completely inhibits the tumor, which correlates positively with the pharmacodynamically regulated dose of p-FGFR3 and reduces KMS11 tumor cell proliferation. Furthermore, AZD4547 was orally administered at a dose of 12.5 mg/kg to the FGFR1 fusion KG1a xenograft model once daily to inhibit 65% of tumor growth. At the effective dose level, AZD4547 does not show anti-angiogenic effects. AZD4547 has no significant effect on blood pressure and therefore lacks anti-KDR activity in vivo. Correspondingly, AZD4547 was orally administered at a dose of 6.25 mg/kg to Cediranib-sensitive xenograft models, including Calu-6, HCT-15, and LoVo, twice daily, with no activity.

AZD4547 acts highly selectively on FGFR1-3, which is more selective than FGFR4. AZD4547 is effective at both wild-type and mutant FGFR tyrosine kinase activity.

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