In vitro baselining of new pyrrolopyrimidine EGFR-TK inhibitors with Erlotinib

Eirik Sundby; Jin Han; Svein Jacob Kaspersen; Bård Helge Hoff

doi:10.1016/j.ejps.2015.08.003

In vitro baselining of new pyrrolopyrimidine EGFR-TK inhibitors with Erlotinib

Eur J Pharm Sci. 2015 Dec 1:80:56-65. doi: 10.1016/j.ejps.2015.08.003. Epub 2015 Aug 19.

Authors

Eirik Sundby¹, Jin Han², Svein Jacob Kaspersen³, Bård Helge Hoff⁴

Affiliations

¹ Sør-Trøndelag University College, E. C. Dahls gt. 2, NO-7004 Trondheim, Norway. Electronic address: Eirik.Sundby@hist.no.
² 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.
³ Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.jacob.kaspersen@chem.ntnu.no.
⁴ Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.no.

PMID: 26296860
DOI: 10.1016/j.ejps.2015.08.003

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy
Caco-2 Cells / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cytochrome P-450 Enzyme Inhibitors / pharmacology
Dose-Response Relationship, Drug
ErbB Receptors / antagonists & inhibitors*
Erlotinib Hydrochloride / pharmacology*
Female
Humans
In Vitro Techniques
Lung Neoplasms / drug therapy
Ovarian Neoplasms / drug therapy
Pyrimidines / pharmacology*
Pyrroles / pharmacology*

Substances

Antineoplastic Agents
Cytochrome P-450 Enzyme Inhibitors
Pyrimidines
Pyrroles
pyrrolopyrimidine
Erlotinib Hydrochloride
ErbB Receptors