Design and synthesis of dual kinase-bromodomain inhibitors targeting ALK and BRD4
Thesis or Dissertation
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Neuroblastoma is a paediatric cancer of neural crest origin and is the most common extracranial tumour in childhood. In high-risk patients with poor clinical outcome, mutations within the kinase domain of anaplastic lymphoma kinase (ALK), such as ALK-F1174L, co-segregate with amplification of the MYCN gene. Transcription of MYCN is directly upregulated by ALK-F1174L, whilst BRD4, a member of the BET family of transcriptional co-regulators is essential for MYCN expression. The project 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. Thus 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. BI-2536, a known dual PLK-1-BRD4 inhibitor with modest potency against ALK, was chosen as the starting point. Using structure based design, analogues of BI-2536 were prepared and tested 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 this work highlights the challenges of designing and developing dual inhibitors; in particular balancing potencies and the physiochemical properties whilst maintaining selectivity against other bromodomains and kinases.
Neuroblastoma - Genetics
Medicinal Chemistry 4
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Institute of Cancer Research (University Of London)