8-Biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) Marine Desage-El Murr a , Celine Cano a , Bernard T. Golding a , Ian R. Hardcastle a , Marc Hummersome b , Mark Frigerio b , Nicola J. Curtin a , Keith Menear b , Caroline Richardson b , Graeme C. M. Smith b , Roger J. Griffin a, * a Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK b KuDOS Pharmaceuticals Ltd, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, UK article info Article history: Received 5 June 2008 Revised 16 July 2008 Accepted 16 July 2008 Available online 20 July 2008 Keywords: DNA-PK Kinase inhibitor DNA-repair Chromenones Cancer abstract The synthesis and biological evaluation of libraries of 8-biarylchromen-4-ones enabled the elucidation of structure–activity relationships for inhibition of the DNA-dependent protein kinase (DNA-PK), with 8-(3- (thiophen-2-yl)phenyl)chromen-4-one and 8-(3-(thiophen-3-yl)phenyl)chromen-4-one being especially potent inhibitors. Ó 2008 Elsevier Ltd. All rights reserved. The cellular response to DNA double-strand break (DSB) forma- tion is an essential component of normal cell survival, following exposure to DNA-damaging chemicals and ionising radiation. 1 The DNA-dependent protein kinase (DNA-PK), a member of the phosphatidylinositol (PI) 3-kinase-related kinase (PIKK) family, plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway. 2–4 The ability of DNA-PK to detect and signal the repair of DNA damage may also protect cancer cells from the cytotoxic effects of DNA-damaging cancer therapies. Accordingly, inhibition of DNA-PK has been demonstrated to potentiate the cytotoxicity of ionising radiation and a number of DSB-inducing antitumour agents in vitro. 5,6 A major objective of our research is the development of potent and selective DNA-PK inhibitors, suitable for clinical evaluation as chemo- and radio-sen- sitisers in the treatment of cancer. In the absence of suitable structural biology information for DNA-PK, inhibitor design has been guided by a combination of homology modelling, utilising the known crystal structure of PI 3-kinase, 7 and pharmacophore mapping based on the non-selec- tive DNA-PK inhibitor LY294002 (1). 8 These initial studies enabled the elucidation of structure–activity relationships (SARs) for DNA- PK inhibition, and the discovery of potent and selective chrome- none inhibitors, exemplified by NU7026 (2). 9 Encouraged by the potency and kinase-selectivity of 2 and related compounds, a sys- tematic variation of the substitution pattern on the chromenone O N O O R O N O O O N O O S 1;R=H 4; R = Ph 2 3 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.07.066 * Corresponding author. Tel./fax: +44 191 222 8591. E-mail address: r.j.griffin@ncl.ac.uk (R.J. Griffin). Bioorganic & Medicinal Chemistry Letters 18 (2008) 4885–4890 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl