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Title: Design and synthesis of chemical probes for the BRPF bromodomains
Author: Igoe, N. M.
ISNI:       0000 0004 7224 7133
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Bromodomains (BRDs) are protein-protein interaction modules responsible for recognition of and binding to ε-N-acetylated histone lysines. Following on from the success in drugging the Bromodomain and extra-terminal (BET) domain BRDs, there has been significant interest in elucidating the biological function of the other ~ 50 BRDs encoded for in the human genome. The BRPF (Bromodomain and Plant homeodomain finger containing) proteins function endogenously as part of a tetramer involved in regulation of gene transcription, by modulating MYST histone acetyl transferase activity. Translocations and aberrant activity of this tetramer have been implicated in a number of aggressive forms of acute myeloid leukemia (AML), however the role the bromodomain plays in the disease progression is currently unclear. To this end, BRPF inhibitors were designed by optimisation of the N-methylquinolin-2(1H)-one (1) fragment hit. A credible, tunable SAR model for the BRPF bromodomains, built on the Nmethylquinolin-2(1H)-one core, was developed which has culminated in the synthesis of NI-42 and NI-57, BRPF biased and BRPF specific probes respectively. Having confirmed the potency and selectivity of NI-42 and NI-57, their pharmacokinetic (PK) profiles were thoroughly investigated highlighting excellent oral and IV PK profiles. Subsequently, the compounds were employed to interrogate the biological consequences of BRPF bromodomain inhibition in a variety of disease models, with some evidence of selective AML cell line growth inhibition being observed. NI-42 will be of most use when used in conjunction with its inactive control NI-198, providing confidence in biological results obtained.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available