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 which is directly upregulated by ALKF1174L , and by BRD4, a member of the BET family of transcriptional co-regulators. The aim of the project is to generate dual ALK/BRD4 inhibitors that target both oncogenic mutations as an effective treatment for these patients. The oncogenic activity of ALKF1174L is targeted via inhibition of the kinase domain, and transcription of MYCN via BRD4 inhibition. 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. We chose BI-2536, a known dual PLK-1/BRD4 inhibitor with modest potency at ALK, as our starting point. We designed and prepared analogues with the aims of increasing ALK activity, decreasing PLK-1 activity and maintaining BRD4 activity. The testing of these compounds has provided insights on how ALK potency can be enhanced, PLK-1 potency decreased, whilst maintaining potent BRD4 binding. This is exemplified by compound CCT368408 which demonstrates a significantly improved ALK/BRD4 profile. 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 dual ALK/BRD4 inhibitors

255th National Meeting (2018)

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