Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759610
Title: Design, synthesis and characterisation of tool inhibitors targeting BLM helicase
Author: Ali, Yusuf I.
ISNI:       0000 0004 7431 6446
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2018
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Abstract:
Helicases, described as 'guardians of the genome', are enzymes that unwind DNA or RNA. Certain helicases, such as Bloom syndrome protein (BLM), are highly implicated in the DNA damage response (DDR). For example, BLM has various roles in homologous recombination (HR), a key pathway in the repair of DNA double strand breaks. Targeting proteins involved in DDR has recently garnered potential as a selective chemotherapeutic strategy. In this work, a tool inhibitor targeting BLM helicase was sought to increase understanding of its role and relevance in DNA damage repair. The only characterised BLM helicase inhibitor, ML216, was developed from the results of a quantitative high-throughput screen (qHTS) screen on BLM helicase.1 This reported inhibitor presented as a good candidate for a starting point in a hit optimisation campaign that ultimately was not successful due to poor physicochemical properties of this compound series. In order to identify a more suitable hit optimisation candidate, 672 actives from the MLSMR qHTS screen [AID2528]2 were analysed and 7 series were selected for in-house synthesis and biological evaluation. This led to the discovery of a single series that is a relatively potent inhibitor of BLM helicase. Hit optimisation primarily focused on the design and synthesis of a highly potent compound with a good solubility profile. Subsequently, co-crystallisation of BLM with this novel series led to the application of rational structure-based methods in the design of tool BLM inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.759610  DOI: Not available
Keywords: QP0616.D54 DNA Helicases
Share: