Combinations of RIPK
The present invention pertains to the treatment of diseases associated with a dysregulated immune response such as auto immune disorders, inflammatory diseases or pathological immune responses as adverse effects of medical treatments. In particular the invention provides a combined use of inhibitors of Receptor-interacting serine/threonine-protein kinase (RIPK1) and inhibitors of Inhibitor of κB (IκB) Kinase (IKK) in subjects suffering from such disorders. The invention provides such inhibitory compounds and their combinations for use in medical applications, as well as pharmaceutical compositions comprising the compounds of the invention.
1 . A method of treating a deregulated immune response in a subject, wherein the deregulated immune response is systemic neutrophilia or increased interleukin-1β (IL-1β) caused as a side effect by inhibiting inhibitor of κB (IκB) kinase (IKK)/nuclear factor κB (NFκB) signaling in a cell of the subject, wherein the method comprises:
inhibiting a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the cell of the subject,
wherein the inhibition of IKK/NFκB signaling comprises administering SPC839, MLN120B, PS1145, SC-514*, IκB kinase inhibitor peptide, [5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1), wedelolactone, N-(3,5-bistrifluoromethylphenyl)-5-chloro-2-hydroxybenzamide (IMD-0354), (5-phenyl-2-ureido)thiophene-3-carboxamide (IKK-2 inhibitor VI), 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-(4-piperidinyl)-3-pyridinecarbonitrile (ACHP), or B1605906 to the subject, and
wherein the inhibition of the RIPK1 comprises administering GSK2982772, necrostatin-1, or necrostatin-1 stable to the subject.
2 . The method of claim 1 , wherein the side effect is increased interleukin-1β (IL-1β) release.
3 . The method of claim 2 , wherein the subject is suffering from an inflammatory disease.
4 . The method of claim 1 , wherein the method comprises the concomitant inhibition of the RIPK 1 and inhibition of IKK/NFκB signaling in the cell of the subject.
5 . The method of claim 2 , wherein the side effect is caused by inhibiting an IKK in the cell of the subject.
6 . The method of claim 5 , wherein the side effect is caused by inhibiting an IKK 2 /IKKβ in the cell of the subject.
7 . The method of claim 1 , wherein the method comprises inhibiting IKK/NFκB signaling in the cell of the subject and then inhibiting the RIPK 1 in the cell of the subject.
8 . The method of claim 1 , wherein the method comprises inhibiting the RIPK1 in the cell of the subject and then inhibiting IKK/NFκB signaling in the cell of the subject.
9 . The method of claim 1 , wherein the systemic neutrophilia is caused by the inhibition of IKK/NFκB signaling in macrophages of the subject.
10 . The method of claim 1 , wherein the kinase activity of the RIPK1 and the IKK/NFκB signaling in a macrophage in the subject are inhibited, thereby suppressing IKK/NFκB signaling dependent IL-1β production in the macrophage.
11 . A method of inhibiting the development of neutrophilia in a subject, wherein the neutrophilia is caused by the inhibition of IKK/NFκB signaling in macrophages of the subject, wherein the method comprises a step of inhibiting RIPK1 in cells of the subject,
wherein the inhibition of IKK/NFκB signaling comprises administering SPC839, MLN120B, PS1145, SC-514*, IκB kinase inhibitor peptide, [5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1), wedelolactone, N-(3,5-bistrifluoromethylphenyl)-5-chloro-2-hydroxybenzamide (IMD-0354), (5-phenyl-2-ureido)thiophene-3-carboxamide (IKK-2 inhibitor VI), 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-(4-piperidinyl)-3-pyridinecarbonitrile (ACHP), or B1605906 to the subject, and
wherein the inhibition of the RIPK1 comprises administering GSK2982772, necrostatin-1, or necrostatin-1 stable to the subject.
12 . A method of suppressing IL-1β production induced by inhibition of IKK/NFκB signaling in a macrophage, the method comprising inhibiting in the macrophage RIPK1 and IKK/NFκB signaling simultaneously,
wherein the inhibition of IKK/NFκB signaling comprises administering SPC839, MLN120B, PS1145, SC-514*, IκB kinase inhibitor peptide, [5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1), wedelolactone, N-(3,5-bistrifluoromethylphenyl)-5-chloro-2-hydroxybenzamide (IMD-0354), (5-phenyl-2-ureido)thiophene-3-carboxamide (IKK-2 inhibitor VI), 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-(4-piperidinyl)-3-pyridinecarbonitrile (ACHP), or B1605906 to the subject, and
wherein the inhibition of the RIPK1 comprises administering GSK2982772, necrostatin-1, or necrostatin-1 stable to the subject.
13 . A method of treating a deregulated immune response in a subject, wherein the deregulated immune response is increased interleukin-10 (IL-1β) caused as a side effect by inhibiting inhibitor of κB (IκB) kinase (IKK)/nuclear factor κB (NFκB) signaling in a cell of the subject, wherein the method comprises:
inhibiting a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the cell of the subject,
wherein the inhibition of IKK/NFκB signaling comprises administering SPC839, MLN120B, PS1145, SC-514*, IκB kinase inhibitor peptide, [5-(p-fluorphenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1), wedelolactone, N-(3,5-bistrifluoromethylphenyl)-5-chloro-2-hydroxybenzamide (IMD-0354), (5-phenyl-2-ureido)thiophene-3-carboxamide (IKK-2 inhibitor VI), 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-(4-piperidinyl)-3-pyridinecarbonitrile (ACHP), or B1605906 to the subject, and
wherein the inhibition of the RIPK1 comprises administering GSK2982772, necrostatin-1, or necrostatin-1 stable to the subject.