Early phase I data on an irreversible pan-erb inhibitor: CI-1033. What did we learn?
CI-1033 (Canertinib dihydrochloride) is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/ MAP kinase, and PI-3 kinase/AKT pathways (Figure 1). CI-1033 is also unique in that it is an irreversible inhibitor; thereby providing prolonged suppression of erbB receptor-mediated signaling. Preclinical data show CI-1033 to be efficacious against a variety of human tumors in mouse xenograft models, including breast carcinomas.
Dewji
M R
MR
Clinical Research & Development - Oncology, Pfizer Global R&D, Sandwich, UK. Raz.Dewji@pfizer.com
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D001682:Biological Availability; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D048868:Adaptor Proteins, Signal Transducing; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C420268:Canertinib