Abstract

New Chemical Probes to Explore Novel Approaches to Treat Alzheimer’s Disease and Cancer

Paul Fish, Head of Chemistry, Alzheimers Research UK, University College London

Established in 2015, the goal of the Alzheimer’s Research UK UCL Drug Discovery Institute (ARUK UCL DDI) is to facilitate the rapid translation of knowledge generated at UCL and partners towards novel therapeutics for neurodegenerative diseases: the dementias, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotropic lateral sclerosis. The ARUK UCL DDI will consist of a team of 25 biologists and chemists tasked with the goal of developing and validating therapeutics for neurodegenerative diseases suitable for progression towards clinical trials. The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit to NI-42 as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over non-class IV BRD proteins. Evaluation of NI-42 in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that NI-42 had properties compatible with oral dosing in mouse models of disease (Fpo 49 %). We propose that NI-42 is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins. Chemical probe NI-42 will be of most value in the interpretation of phenotypic assays when used in conjunction with the inactive control NI-198 and with other available chemical probes of the class IV BRDs.