title: In vitro baselining of new pyrrolopyrimidine EGFR-TK inhibitors with Erlotinib.
abstract: 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.
authors: Sør-Trøndelag University College, E. C. Dahls gt. 2, NO-7004 Trondheim, Norway. Electronic address: Eirik.Sundby@hist.no.
authors: Eirik
authors: E
authors: Sundby
authors: Sør-Trøndelag University College, E. C. Dahls gt. 2, NO-7004 Trondheim, Norway; Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Jin.han@chem.ntnu.no.
authors: Jin
authors: J
authors: Han
authors: Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.jacob.kaspersen@chem.ntnu.no.
authors: Svein Jacob
authors: SJ
authors: Kaspersen
authors: Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.no.
authors: Bård Helge
authors: BH
authors: Hoff
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D018938:Caco-2 Cells / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
keywords: 2-[[6-[4-(Hydroxymethyl)-2-methoxyphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-2-phenylethanol (PubChem CID: 90466098); ADME; Cancer; Dasatinib (PubChem CID: 3062316); EGFR-TK; Erlotinib; Erlotinib (PubChem CID: 176870); Lapatinib (PubChem CID: 208908); Pyrrolopyrimidine; Tyrosine kinase