881375-00-4

Usage

Uses

KU-0060648 is a dual inhibitor of DNA-PK and PI3Kα, PI3Kβ, PI3Kδ.

Upstream product

• 881375-80-0 2-morpholino-8-(1-nitrodibenzo[b,d]thiophen-4-yl)-4H-chromen-4-one 
• 881375-81-1 8-(1-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one 
• 5308-25-8 4-ethylpiperazine 
• 881375-83-3 2-chloro-N-[4-(2-morpholin-4-yl-4-oxo-4H-chromen-8-yl)-dibenzothiophen-1-yl]-acetamide 
• 132-65-0 dibenzothiophene 
• 24444-75-5 4-hydroxydibenzothiophene 
• 24444-74-4 4-methoxydibenzothiophene 
• 24444-76-6 4-methoxy-1-nitrodibenzothiophene 
• 881375-77-5 1-nitrodibenzothiophen-4-ol 
• 881375-78-6 trifluoromethanesulfonic acid 1-nitrodibenzothiophen-4-yl ether 
• 881375-79-7 4,4,5,5-tetramethyl-2-(1-nitrodibenzo[b,d]thiophen-4-yl)-1,3,2-dioxaborolane 

Relevant academic research and scientific papers

1-substituted (dibenzo[ b,d ]thiophen-4-yl)-2-morpholino-4 h -chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity

Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC 50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH2)nNR1R 2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4- (2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC50 = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.

DNA-PK INHIBITORS

A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20heterocyclyl group, or C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; Q is -NH-C(=O)- or -O-; Y is an optionally substituted C1-5 alkylene group; X is selected from SR3 or NR4R5, wherein, R3, or R4 and R5 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R4 and R5 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; if Q is -O-, X is additionally selected from -C(=O)-NR6R7, wherein R6 and R7 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R6 and R7 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and if Q is -NH-C(=O)-, -Y-X may additionally be selected from C1-7 alkyl.