Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase

Sonali Kurup,Bradley Mcallister,Pavlina Liskova,Trusha Mistry,Anthony Fanizza,Dan Stanford,Jolanta Slawska,Ulrich Keller,Alexander Hoellein

doi:10.1080/14756366.2017.1376666

Abstract

Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1–18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1–18 allow for a structure–activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4-methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition.

Highlights

Dysfunctional epidermal growth factor receptor kinase (EGFR) plays a role in tumour progression and angiogenesis in squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC) and colorectal cancer[1,2]
It was of interest to determine if a single molecule could be developed for dual Aurora kinase A (AURKA) and EGFR inhibition based on the crosstalk between EGFR and AURKA and the development of resistance to single EGFR inhibitors
Compound 2 and 7 that included a 30bromo and a 30-bromo, 40-chloro substitution on the 4-anilino moiety respectively provided the most potent EGFR inhibition followed by compounds [3, 5] and 11

Summary

Introduction

Dysfunctional epidermal growth factor receptor kinase (EGFR) plays a role in tumour progression and angiogenesis in squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC) and colorectal cancer[1,2]. Tumours have redundant signaling pathways for tumour progression and often develop resistance to single EGFR inhibitors[3]. One of the mechanisms of resistance to cetuximab in SCCHN has been redundant signaling mediated by aurora kinases[4,5]. Hoellein et al.[6] demonstrated that resistance to cetuximab in SCCHN can be overcome when given in combination with the AURKA inhibitor, alisertib. Chen et al.[8] showed that AURKA upregulation played a role in gefitinib sensitivity in NSCLC cells and suggested that AURKA and EGFR inhibitors given in combination could be effective. Zhang et al.[9] reported that combination therapy with erlotinib and alisertib had synergistic effects in lung cancer cell lines in vitro and in vivo. Dual inhibition of EGFR and AURKA could offer synergistic mechanisms to overcome resistance and suppress tumours such as SCCHN and NSCLC where redundancy in EGFR and AURKA signaling is observed[6–9]. It was of interest to determine if a single molecule could be developed for dual AURKA and EGFR inhibition based on the crosstalk between EGFR and AURKA and the development of resistance to single EGFR inhibitors

Methods

Results

Conclusion