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KR-20260062773-A - METHIONINE SULFOXIDE REDUCTASE B1 INHIBITORS AND ANTICANCER COMPOSITION COMPRISING THE SAME

KR20260062773AKR 20260062773 AKR20260062773 AKR 20260062773AKR-20260062773-A

Abstract

The present invention relates to a methionine sulfoxide reductase B1 inhibitor and an anticancer composition containing the same, and more specifically, to an MsrB1 inhibitor, 4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide or 6-chloro-10-(4-ethylphenyl)-4-hydroxypyrimido[4,5-b]quinolin-2(10H)-one, and an anticancer composition containing the same It is about. In this invention, a novel MsrB1 inhibitor was selected, and it was confirmed that the MsrB1 inhibitor of this invention inhibits differentiation into tumor-friendly M2 macrophages and inhibits tumor growth. In other words, since it was confirmed that the MsrB1 inhibitor of this invention exhibits an anticancer effect through immune control in the tumor microenvironment, it can be usefully utilized as a composition for cancer treatment.

Inventors

  • 이병천
  • 윤상원

Assignees

  • 고려대학교 산학협력단

Dates

Publication Date
20260507
Application Date
20250107
Priority Date
20241025

Claims (8)

  1. Inhibiting methionine sulfoxide reductase B1 (MsrB1) activity, 4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide (4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide) represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] .
  2. Inhibiting methionine sulfoxide reductase B1 (MsrB1) activity, 6-chloro-10-(4-ethylphenyl)-4-hydroxypyrimido[4,5-b]quinolin-2(10H)-one) represented by the following chemical formula 2 or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] .
  3. 4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide (4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide) represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and A pharmaceutical composition for the prevention or treatment of cancer comprising, as an active ingredient, one or more methionine sulfoxide reductase B1 (MsrB1) inhibitors selected from the group consisting of 6-chloro-10-(4-ethylphenyl)-4-hydroxypyrimido[4,5-b]quinolin-2(10H)-one represented by the following chemical formula 2 or pharmaceutically acceptable salts thereof: [Chemical Formula 1] [Chemical Formula 2] .
  4. In paragraph 3, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the above-mentioned MsrB1 inhibitor inhibits M2 differentiation and activity of macrophages and promotes M1 differentiation.
  5. In paragraph 3, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the above cancer is lung cancer, pancreatic cancer, brain tumor, liver cancer, blood cancer, skin cancer, colorectal cancer, bone marrow cancer, breast cancer, osteosarcoma, melanoma, blood cancer, or rectal cancer.
  6. 4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide (4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide) represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and A health functional food composition for the prevention or improvement of cancer, comprising as an active ingredient one or more methionine sulfoxide reductase B1 (MsrB1) inhibitors selected from the group consisting of 6-chloro-10-(4-ethylphenyl)-4-hydroxypyrimido[4,5-b]quinolin-2(10H)-one represented by the following chemical formula 2 or pharmaceutically acceptable salts thereof: [Chemical Formula 1] [Chemical Formula 2] .
  7. In paragraph 6, A health functional food composition for the prevention or improvement of cancer, characterized in that the above MsrB1 inhibitor inhibits M2 differentiation and activity of macrophages and promotes M1 differentiation.
  8. In paragraph 6, A health functional food composition for the prevention or improvement of cancer, characterized in that the above cancer is lung cancer, pancreatic cancer, brain tumor, liver cancer, blood cancer, skin cancer, colorectal cancer, bone marrow cancer, breast cancer, osteosarcoma, melanoma, blood cancer, or rectal cancer.

Description

Methionine Sulfoxide Reductase B1 Inhibitors and Anticancer Composition Comprising the Same The present invention relates to a methionine sulfoxide reductase B1 inhibitor and an anticancer composition containing the same, and more specifically, to an MsrB1 inhibitor, 4-[3-(4-ethylphenyl)-5-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonamide or 6-chloro-10-(4-ethylphenyl)-4-hydroxypyrimido[4,5-b]quinolin-2(10H)-one, and an anticancer composition containing the same It is about. Aerobic organisms that breathe oxygen utilize oxygen molecules as terminal transporters in the process of oxidative phosphorylation for energy production, generating reactive oxygen species in the process. Due to their high reactivity, reactive oxygen species such as superoxide anions and hydroxyl radicals affect the integrity of DNA, proteins, and cell membranes in vivo; they can cause damage by damaging nucleic acids to induce mutations or by causing structural changes in proteins and lipids through oxidation (Schallreuter, KU, et al. , Biochemical and biophysical research communications , 342(1):145-152, 2006). Recently, it has been reported that the absence of reactive oxygen species in vivo or the loss of homeostasis affects aging and related diseases, and that reactive oxygen species not only play a negative role in the body but are also involved in intracellular signaling processes and metabolic regulation (Sauer, H. and M. Wartenberg, Antioxidants & redox signaling , 7(11-12):1423-1434, 2005). To prevent protein damage caused by reactive oxygen species, organisms express antioxidant enzymes such as superoxide dismutase and glutathione; one of these antioxidant enzymes, methionine sulfoxide reductase (Msr), plays a role in reducing methionine sulfoxide (MetO), the oxidized form, to methionine (Met). Since methionine residues, along with cysteine, are sulfur-containing amino acids and are sensitive to oxidative stress, they are easily oxidized to MetO; therefore, organisms have developed a mechanism to reduce Met residues through Msr (Kantorow, M., et al. , Proceedings of the National Academy of Sciences , 101(26):9654-9659, 2004). In addition, it has recently been reported that the reversible regulation of MetO through Msr plays a protective role against oxidative stress as well as regulating biological processes (Lim, JM, et al. , Neurochemical research , 44: 247-257, 2019). In mammals, methionine sulfoxide reductase B1 (MsrB1) is a selenoprotein located in the cytoplasm and nucleus that reduces Met-RO back to methionine in proteins. Studies have been conducted on the association between MsrB1 and innate immunity, and it has been reported that macrophages, the major constituent cells of innate immunity, reconstruct the structural framework for external antigen responses through the mutual regulation of Mical and MsrB1 (Lee, BC, et al. , Molecular cell , 51(3):397-404, 2013). In addition, it has been suggested that MsrB1 may be involved in the inhibition and regulation of inflammatory responses through cytokine secretion, as the expression of anti-inflammatory cytokines such as IL-10 and IL-1ra decreases and the expression of inflammatory cytokines such as IL-12a and IL-12b increases when MsrB1 is deleted (Lee, BC, et al. , Scientific reports , 7(1): 5119, 2017). In addition to macrophages, the role of MsrB1 in dendritic cells, another component of innate immunity, has been investigated. In dendritic cells, MsrB1 influences cell maturation and antigen presentation, activation of co-stimulatory functions, IL-12 production and STAT6 activation, and differentiation into Th1 cells (Lee, H.-J., et al. , Antioxidants , 9(10): 1021, 2020). Furthermore, since methionine can directly donate methyl groups and methyl groups are necessary for DNA synthesis, the possibility that MsrB1 is involved in the growth of cancer cells has been investigated (Szende, B. and E. Tyihak, Cell Biology International , 34(12):1273-1282, 2010). Figure 1 is data verifying the MsrB1 inhibitor, which indirectly determines the activity of MsrB1 by measuring NADPH consumption to confirm inhibitor activity. Figure 2 is data confirming that differentiation into M2 macrophages was inhibited using the M2 marker (CD206) when an MsrB1 inhibitor was administered after stimulation with TCM. Figure 3 shows data confirming that mRNA expression of M2 macrophage-related markers IL-10 and Arg1 was suppressed when an MsrB1 inhibitor was administered after stimulation with TCM. Gene expression levels were compared after standardization with GAPDH. Figure 4 shows data confirming that phosphorylation of CREB (cAMP Response Element-Binding Protein), a well-known tumor-friendly transcription factor, was inhibited when macrophages and tumor cells were co-cultured and then treated with an MsrB1 inhibitor. Figure 5 is data confirming that tumor growth was inhibited when an animal model of a xenograft tumor was treated with an MsrB1 inhibitor or MsrB1 knockout was perfo