Abstract 3238: Design, synthesis and evaluation of a novel series of BLM helicase inhibitors
Authors: Ali Yusuf , Chen Xiangrong , Ward Simon , Pearl Frances 
Published: July 2017

Helicases are enzymes that unwind DNA or RNA. As a result, they are described as ‘guardians of the genome’ and play roles in key processes such as DNA replication, RNA transcription, translation, DNA repair and DNA recombination. Certain helicases have also been implicated in the DNA damage response (DDR) and with an increasing interest growing in these enzymes, more helicases are likely to be implicated in DNA damage repair as understanding grows. Targeting proteins involved in DDR has recently gained promise as a selective chemotherapeutic strategy due to the high level of genomic instability in cancer cells. One of these helicases, Bloom syndrome protein (BLM), is particularly implicated in homologous recombination (HR), a key pathway in the repair of double strand breaks. The role of BLM in DNA repair and its complex interactions with key proteins in these networks suggest it may be a good chemotherapeutic target. The first BLM helicase inhibitor to be characterised was ML216. However, ML216 does not seem to be highly specific to BLM as it also inhibits DNA unwinding of the closely related WRN helicase. Furthermore, the poor solubility and permeability of this series which would prevent reliable in-vitro data from being generated. Potent and selective inhibitors targeting BLM helicase can increase understanding of its function in human cells and role and relevance in DNA damage repair. Furthermore, the tool can also be used in synthetic lethality screens to assess the potential of BLM inhibition as a chemotherapeutic option. As a result, the discovery of a novel series of potent and selective BLM inhibitors with improved physiochemical properties were sought. In this work, 672 active hits of the NIH Molecular Libraries Small Molecule Repository (MLSMR) qHTS screen on BLM helicase, which have been deposited in the PubChem BioAssay database [AID2386], were analysed and 10 series were selected for in-house testing on a BLM helicase unwinding assay. This led to the medicinal chemistry investigation of a single series that is relatively potent compared to inhibitors of other human helicases. Efforts have been undertaken to establish primary SAR and to improve the activity of the compound to &lt;0.1 µM as well as further improve the physiochemical properties of this series. This series has shown positive binding data using microscale thermophoresis (MST). Very few inhibitors of human helicases have used biophysical techniques to validate binding and the use of MST for this purpose has not been reported. Further biological efforts are underway to validate the series through in vitro SCE assays and co-crystallisation methods.

Citation Format: Yusuf Ali, Xiangrong Chen, Simon Ward, Frances Pearl. Design, synthesis and evaluation of a novel series of BLM helicase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3238. doi:10.1158/1538-7445.AM2017-3238