In vitro baselining of new pyrrolopyrimidine EGFR-TK inhibitors with Erlotinib.
Epidermal growth factor receptor tyrosine kinase inhibitors are useful in treatment of non-small cell lung cancer, and show promise in combination therapy settings. Two novel chiral pyrrolopyrimidines have been baselined towards Erlotinib, Lapatinib and Dasatinib using in vitro cellular studies and ADME profiling. One of these, (S)-2-((6-(4-(hydroxymethyl)-2-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-phenylethan-1-ol, was more active than Erlotinib in lung and breast cancer cell models. The compound also had promising activity towards ovarian cancer cell lines, while low activity was seen towards cells of haematological origin. ADME profiling revealed good solubility, higher metabolic stability than Erlotinib and no inhibitory effect towards the hERG voltage-gated ion channel. Investigation of inhibitory potency towards 6 CYP isoforms generally revealed low inhibitory potency, but in the case of CYP3A4, a substrate dependent inhibition was noted using testosterone as substrate (IC50: 12.5μM). No cellular or gene toxicity was noted for the compounds or products of phase I metabolism. However, permeability studies using Caco-2 cells revealed a high efflux ratio. Further experiments using ABC transporter inhibitors revealed that the pyrrolopyrimidines are actively transported by the breast cancer resistant protein and P-glycoprotein transporters, which might prevent their further development into drugs.
['Sundby|Eirik|E|', 'Han|Jin|J|', 'Kaspersen|Svein Jacob|SJ|', 'Hoff|Bård Helge|BH|']
D000970:Antineoplastic Agents D001943:Breast Neoplasms D018938:Caco-2 Cells D045744:Cell Line, Tumor D049109:Cell Proliferation D065607:Cytochrome P-450 Enzyme Inhibitors D004305:Dose-Response Relationship, Drug D066246:ErbB Receptors D000069347:Erlotinib Hydrochloride D005260:Female D006801:Humans D066298:In Vitro Techniques D008175:Lung Neoplasms D010051:Ovarian Neoplasms D011743:Pyrimidines D011758:Pyrroles
Pyrrolopyrimidine EGFR-TK Erlotinib Tyrosine kinase Cancer ADME 2-[[6-[4-(Hydroxymethyl)-2-methoxyphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-2-phenylethanol (PubChem CID: 90466098) Dasatinib (PubChem CID: 3062316) Erlotinib (PubChem CID: 176870) Lapatinib (PubChem CID: 208908)