Mavelertinib是一种选择性的，口服有效的且不可逆的EGFR酪氨酸激酶抑制剂(EGFRTKI)，对Del，L858R和双重突变体T790M/L858R和T790M/Del的IC50值分别为5、4、12和3nM。Mavelertinib可用于非小细胞肺癌(NSCLC)的研究。
Mavelertinib is a selective, orally available and irreversible EGFR tyrosine kinase inhibitor (EGFR TKI), with IC50s of 5, 4, 12 and 3 nM for Del, L858R, and double mutants T790M/L858R and T790M/Del, respectively. Mavelertinib can be used for the research of non-small-cell lung cancer (NSCLC)[1][2][3][4].
Mavelertinib exhibits selectivity over wild-type EGFR (IC50=307 nM)[1].Mavelertinib (10 μM) exhibits less than 50% e?ect or inhibition against all nonkinase targets[1].Mavelertinib inhibits the hERG26 current with an IC50 > 100 μM[1].
Mavelertinib exhibits low to moderate oral bioavailability (mouse 60%, rat 11%, dog 66%) following oral administration (mouse 1, rat 30, dog 3 mg/kg)[1].Mavelertinib exhibits short plasma half-lives (mouse 0.56, rat 0.28, dog 1.3 h) due to moderate to high plasma clearance (mouse 53, rat 49, dog 12 mL/min/kg) and low steady-state volume of distribution (mouse 1.48, rat 0.66, dog 0.94 L/kg) following intravenous administration (1 mg/kg to mouse, rat and dog)[1]. Animal Model: Female Nu/Nu mice[1]
[1]. Planken S, et, al. Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR. J Med Chem. 2017 Apr 13;60(7):3002-3019. [2]. Murtuza A, et, al. Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer. Cancer Res. 2019 Feb 15; 79(4): 689-698. [3]. Patel H, et, al. Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance. Eur J Med Chem. 2017 Dec 15; 142:32-47. [4]. Husain H, et, al. First-in-human phase I study of PF-06747775, a third-generation mutant selective EGFR tyrosine kinase inhibitor (TKI) in metastatic EGFR mutant NSCLC after progression on a first-line EGFR TKI. Annals of Oncology. 2017 Sep.
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