Neuroblastoma is a paediatric cancer of neural crest origin and is the most common extracranial solid tumour in childhood. In high-risk patients with poor clinical outcome, mutations within the kinase domain of anaplastic lymphoma kinase (ALK), such as ALKF1174L, co-segregate with amplification of the MYCN gene. Transcription of MYCN is directly upregulated by ALKF1174L, whilst BRD4, a member of the BET family of transcriptional co-regulators is essential for MYCN expression. Our hypothesis is that a dual ALK-BRD4 inhibitor is beneficial compared with single inhibitors of ALK and BRD4, avoiding the need for combinatorial trials and treatment. The aim of the project is to generate dual ALK-BRD4 inhibitors that target both oncogenic mutations as an effective treatment for high-risk neuroblastoma patients. We chose BI-2536 a known dual PLK-1-BRD4 inhibitor with modest potency against ALK as our starting point. Using structure based design, we prepared and tested analogues with the aims of increasing ALK activity, decreasing PLK-1 activity and maintaining BRD4 activity. The testing of these compounds has provided SAR on how the potency can be modulated at ALK, BRD4 and PLK-1. This work has led to a series of compounds with significantly improved dual ALK-BRD4 profiles, favourable kinase and bromodomain selectivity and on-target activity in cells. Furthermore our work highlights the challenges of designing and developing dual inhibitors; in particular balancing dual inhibition with the physicochemical properties whilst maintaining selectivity against other bromodomains and kinases.

Design and synthesis of a dual kinase-bromodomain inhibitor targeting ALK and BRD4

2019 Spring National Meeting

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