"目录号: HY-15196

JAK/STAT SignalingProtein Tyrosine Kinase/RTK-

TAK-285是HER2和EGFR(HER1)抑制剂，IC50为17 nM和23 nM，比对HER4的抑制性高10倍以上，对MEK1/5，c-Met，Aurora B，Lck和CSK的抑制性较低。

EGFR

相关产品

AZD-9291-Gefitinib-Lapatinib-Afatinib-Erlotinib-AG-490-Genistein-AG-1478-Neratinib-EGF816-Olmutinib-AZD3759-Dacomitinib-Irbinitinib-CO-1686-

生物活性

Description

TAK-285 is a novel dual HER2 and EGFR(HER1) inhibitor with IC50 of 17 nM and 23 nM, >10-fold selectivity for HER1/2 than HER4, less potent to MEK1/5, c-Met, Aurora B, Lck, CSK etc. IC50 value: 17/23 nM (HER2/1) [1]Target: HER1/2in vitro: MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and Lyn B with IC50 of 1.1 μM, 5.7 μM, 4.2 μM, 1.7 μM, 2.4 μM, 4.7 μM, and 5.2 μM, respectively, and displays no activity against other kinases with IC50 of >10 μM. TAK-285 shows significant growth inhibitory activity against BT-474 cells (HER2-overexpressing human breast cancer cell line) with GI50 of 17 nM [1].  Compared with SYR127063 a potent inhibitor of HER2, TAK-285 displays similar in vitro potency against HER2 and EGFR. Compared with the full cytoplasmic domains of the wild-type proteins, the mutations and shortened boundaries used for structure determination of HER2-KD and EGFR-KD do not significantly change the inhibitory activity (IC50) of TAK-285. TAK-285 binds to the inactive conformation of EGFR, and shows a similar binding mode with lapatinib in the active site [2]. in vivo: The oral bioavailability of TAK-285 is 97.7% in rats and 72.2% in mice at a dose of 50 mg/kg. Oral administration of TAK-285 at 100 mg/kg twice daily for 14 days displays significant antitumor efficacy in the HER2-overexpressing BT-474 tumor xenograft mouse model with tumor/control (T/C) ratio of 29%, without affecting body weight. Similar to the BT-474 model, TAK-285 exhibits dose-dependent tumor growth inhibition of 4-1ST (HER2-overexpressing human gastric cancer tumor) xenografts in mice, with T/C of 44% and 11% at doses of 50 mg/kg and 100 mg/kg, twice daily, respectively, without significant body weight loss in mice [1]. After oral administration of TAK-285, a significant amount of TAK-285 is present in the brain of rats in pharmacologically active, unbound form (approximately 20% of its free plasma level), indicating that TAK-285 has a potential in the therapy of CNS malignancies/metastases [3].

Clinical Trial

NCT00535522

Millennium Pharmaceuticals, Inc.

Cancer

August 2007

Phase 1

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References

[1].Ishikawa T, et al. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold. J Med Chem, 2011, 54(23), 8030-8050.

[2].Aertgeerts K, et al. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J Biol Chem, 2011, 286(21), 18756-18765.

[3].Erdo F, et al. Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in rats. Brain Res Bull, 2012, 87(4-5), 413-419.