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US 11,028,084 B2Granted
Selective inhibitors of gentotoxic steress-induced IKK/NF-κB pathways
AssigneesMax-DelbrüCk-Centrum FüR Molekulare Medizin In Der Helmholtz-Gemeinschaft, Forschungsverbund Berlin E.V.
InventorsClaus Scheidereit, Michael Willenbrock, Peter Lindemann, Silke Radetzki, Jens-Peter Von Kries, Marc Nazare
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Abstract
A method is for treatment of a disease associated with genotoxic stress-induced inhibitor of nuclear factor-κB kinase/nuclear factor kappa-light chain enhancer of activated B cells (IKK/NF-κB) signaling. The method can include administering a compound to a subject having a cancer exhibiting genotoxic stress induced IKK/NF-κB activation.
Claims19
A method of treatment of a cancer in a subject in need thereof comprising:
- (a) identifying the subject as having a cancer exhibiting genotoxic stress-induced IKK/NF-κB signaling activation that causes growth of the cancer,
- (b) selectively blocking activation of IKK/NF-κB in response to the genotoxic stress upstream of the IKK complex in the subject without blocking NF-κB activation upon signaling caused by other pathways in the subject by administering to the subject a compound according to Formula I,
- wherein
- R1=H, O;
- R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide;
- R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms;
- X1 and X2=N or C;
- X3=C;
- ring A is an aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms selected from the group consisting of O and N,
- wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, alkoxycarbonyl, amine, aryl, (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine) and alkoxyamine;
- the bond z may be present or not present, wherein when bond z is not present:
- the C of bond z of ring C is potentially substituted with R3, and X3 of the A ring is optionally substituted with H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine.
9 more elements
Compound according to Formula I,
- wherein:
- R1=0;
- R5=H, halogen, C1-C5 alkyl or alkoxy, or amine;
- R6=H, OH, halogen, C1-C5 alkyl or alkoxy;
- R7=H, halogen, C1-C5 alkyl or alkoxy;
- R8=halogen, C1-C5 alkyl or alkoxy,
- wherein at least one of R5 to R8 is not H;
- R9=H, halogen, or C1-C5 alkyl or alkoxy;
- R10=H, halogen, or C1-C5 alkyl or alkoxy;
- R11=H, halogen, C1-C5 alkyl, alkoxy or carbonyl;
- R12=H, halogen, or C1-C5 alkyl or alkoxy;
- or wherein when X1 is C, R9 and R10, R10 and R11, R11 and R12, or R12 and the C in the position of bond z of ring C, form an optionally aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms or forming phenyl;
- X1=N or C;
- X3=C;
- ring A is a heteroaromatic cyclic structure of 6 members, comprising 1 or 2 heteroatoms selected from 0 and/or N,
- wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl and alkoxyamine;
- the bond z may be present or not present, wherein when bond z is not present;
- and
- the C in the position of bond z of ring C is substituted with halogen or C1-C5 alkyl, or X3 of the A ring is optionally substituted with H, C1-C5 alkyl, OH or halogen.
16 more elements
Dependencies are inferred from the claim text.