PF-06747775

Names

[ Name ]:
PF-06747775

[Synonym ]:
2-Propenamide, N-[(3R,4R)-4-fluoro-1-[6-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-9-methyl-9H-purin-2-yl]-3-pyrrolidinyl]-
MFCD29079007
YXX2180047
N-[(3R,4R)-4-Fluoro-1-{6-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-9-methyl-9H-purin-2-yl}-3-pyrrolidinyl]acrylamide
Mavelertinib
UNII:YXX2180047

Biological Activity

[Description]:

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].

[Related Catalog]:

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> EGFR

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> EGFR

[Target]

IC50: 3 nM (T790M/Del), 4 nM (L858R), 5 nM (Del), 12 nM (T790M/L858R), 307 nM (wild-type)[1]

[In Vitro]

Mavelertinib exhibits selectivity over wild-type EGFR (IC50=307 nM)[1]. Mavelertinib (10 μM) exhibits less than 50% eﬀect or inhibition against all nonkinase targets[1]. Mavelertinib inhibits the hERG26 current with an IC50 > 100 μM[1].

[In Vivo]

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] Dosage: 1 mg/kg (Pharmacokinetic Analysis) Administration: P.o. and i.v. administration Result: Oral bioavailability (60%), T1/2 (1.48 h).

[References]

[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.