KU-0060648   Click here for help

GtoPdb Ligand ID: 8011

Synonyms: KU 0060648
Compound class: Synthetic organic
Comment: KU-0060648 is a dual inhibitor of DNA dependent protein kinase (DNA-PK) and the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) α, β and δ subunits. This compound is an analogue of NU-7441 with improved solubility and potency, and additional activity against PI3Ks [1]. This is compound 39 in Cano et al. (2013) [1].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 7
Topological polar surface area 106.5
Molecular weight 582.23
XLogP 5.92
No. Lipinski's rules broken 1
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Canonical SMILES CCN1CCN(CC1)CC(=O)Nc1ccc(c2c1c1ccccc1s2)c1cccc2c1oc(cc2=O)N1CCOCC1
Isomeric SMILES CCN1CCN(CC1)CC(=O)Nc1ccc(c2c1c1ccccc1s2)c1cccc2c1oc(cc2=O)N1CCOCC1
InChI InChI=1S/C33H34N4O4S/c1-2-35-12-14-36(15-13-35)21-29(39)34-26-11-10-23(33-31(26)25-6-3-4-9-28(25)42-33)22-7-5-8-24-27(38)20-30(41-32(22)24)37-16-18-40-19-17-37/h3-11,20H,2,12-19,21H2,1H3,(H,34,39)
No information available.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
DNA-dependent protein kinase (DNA-PK) activity is essential for repair of DNA double-strand breaks [5]. Inhibition of DNA-PK sensitises cells to chemo- or radio-therapy agents [2,4], leading to increased DNA damage being induced by these types of cancer therapies. DNA-PK is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family involved in the signalling of cellular stress responses, which also includes the mammalian proteins ATM, ATR, mTOR and hSMG1 [2,6]. By inhibiting DNA-PK and PI3K activity, KU-0060648 sensitises tumour cells to DNA damaging chemotherapeutics and increases cell death [3].