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EP-4740960-A1 - DRUG FOR TREATING TUMOR HAVING TP53 GENE MUTATION

EP4740960A1EP 4740960 A1EP4740960 A1EP 4740960A1EP-4740960-A1

Abstract

Disclosed in the present invention is a drug for treating a tumor having a TP53 gene mutation. The drug comprises a thymine DNA glycosidase (TDG for short, the same below) inhibitor and a pharmaceutically acceptable auxiliary component. The TDG inhibitor used in the present invention can effectively inhibit human TDG protein expression and thus has a good treatment effect on a tumor having a TP53 gene mutation.

Inventors

  • XU, GUOLIANG
  • WU, HAIPING

Assignees

  • Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
  • Cytosinlab Therapeutics Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240703

Claims (14)

  1. Use of a TDG inhibitor for the preparation of a pharmaceutical composition for the treatment of tumors associated with TP53 gene mutations; wherein the pharmaceutical composition comprises a therapeutically effective amount of the TDG inhibitor and pharmaceutically acceptable excipients thereof.
  2. The use of claim 1, wherein the TP53 gene mutations are selected from the group consisting of missense mutation, gene deletion, frameshift mutation, splice site mutation, and truncation mutation.
  3. The use of claim 1, wherein the TDG inhibitor is an inhibitor targeting the human TDG (GENE ID: 6996).
  4. The use of claim 1, wherein the TDG inhibitor is selected from the group consisting of small molecule inhibitors, polypeptide drugs, sgRNA compositions targeting the human TDG for use in CRISPR-Cas9 gene knockout technology, siRNA targeting the human TDG sequence for use in RNA interference technology and combinations thereof, shRNA targeting the human TDG sequence for use in RNA interference technology and combinations thereof.
  5. The use of claim 1, wherein the TDG inhibitor is an sgRNA targeting the human TDG sequence for use in CRISPR-Cas9 gene knockout technology, and the sgRNA is selected from the group consisting of (each presented 5' to 3') : 1 sg-1: GCTATAAAACTGGAAGTTAG 2 sg-2: TGTATTTCAGAGGCTCCAAA 3 sg-3: ACGAAATATGGACGTTCAAG 4 sg-4: TGGGTCATCCACTGCCCATT 5 sg-5: TGGCATAAACCCGGGACTAA 6 sg-6: TTTGACCTACAGCTTGCCCA 7 sg-7: GTTGAGAGCGTGGAGTTAAG 8 sg-8: TGAGGTCCAGCTGAACCATA 9 sg-9: GGGCATCATTACCCTGGACC 10 sg-10: CTACCAGGGAAGTATGGTAT.
  6. The use of claim 1, wherein the TDG inhibitor is an siRNA targeting the human TDG sequence for use in RNA interference technology, and the siRNA is selected from the group consisting of (each presented 5' to 3'): 11 si-1S: GAACGAAAUAUGGACGUUCAA 12 si-1AS: UUGAACGUCCAUAUUUCGUUC 13 si-2S: GGACUUAAGAGAUCAGUUGAA 14 si-2AS: UUCAACUGAUCUCUUAAGUCC 15 si-3A: GGUUAUGAGGCAGCAUAUGGU 16 si-3AS: ACCAUAUGCUGCCUCAUAACC 17 si-4A: CAGCUAUUCCCUUCAGCAA 18 si-4AS: UUGCUGAAGGGAAUAGCUG 19 si-5A: CCAGAACAACAGAACCAAA 20 si-5AS: UUUGGUUCUGUUGUUCUGG 21 si-6A: GGAUGAUCACACUCUACCA 22 si-6AS: UGGUAGAGUGUGAUCAUCC 23 si-7A: GCAAAGAUCUCUCCAGUAA 24 si-7AS: UUACUGGAGAGAUCUUUGC 25 si-8A: GAAGGAGGACGUAUUCUAGUA 26 si-8AS: UACUAGAAUACGUCCUCCUUC 27 si-9A: GACGUAUUCUAGUACAGAA 28 si-9AS: UUCUGUACUAGAAUACGUC 29 si-10A: CACGAAUAGCAGUGUUUAA 30 si-10AS: UUAAACACUGCUAUUCGUG 31 si-11A: GAAACUCUCUGCUAUGUUA 32 si-11AS: UAACAUAGCAGAGAGUUUC 33 si-12A: GACAAAGUUCAUUACUACA 34 si-12AS: UGUAGUAAUGAACUUUGUC 35 si-13A: GAAGGACUUAAGAGAUCAGUU 36 si-13AS: AACUGAUCUCUUAAGUCCUUC 37 si-14A: GACUUAAGAGAUCAGUUGA 38 si-14AS: UCAACUGAUCUCUUAAGUC 39 si-15A: GAAAGGCAUUGAACGAAAUAU 40 si-15AS: AUAUUUCGUUCAAUGCCUUUC 41 si-16A: GGACGUUCAAGAGGUGCAA 42 si-16AS: UUGCACCUCUUGAACGUCC 43 si-17A: GUUCAAGAGGUGCAAUAUA 44 si-17AS: UAUAUUGCACCUCUUGAAC 45 si-18A: GCAAUAUACAUUUGACCUA 46 si-18AS: UAGGUCAAAUGUAUAUUGC 47 si-19A: GGUGGUGCUUACGGAGAAA 48 si-19AS: UUUCUCCGUAAGCACCACC 49 si-20A: GGAGUUAAGAGGAGAAUCA 50 si-20AS: UGAUUCUCCUCUUAACUCC 51 si-21A: GACCAAAUUCCUUCCUUUA 52 si-21AS: UAAAGGAAGGAAUUUGGUC; in the above nucleic acid sequences, U nucleotides and T nucleotides are interchangeable.
  7. The use of claim 1, wherein the TDG inhibitor is an shRNA targeting the human TDG sequence for use in RNA interference technology, and the shRNA is selected from the group consisting of (each presented 5' to 3'): 53 sh-1A: 54 sh-1AS: 55 sh-2A: 56 sh-2AS: 57 sh-3A: 58 sh-3AS: 59 sh-4A: 60 sh-4AS: 61 sh-5A: 62 sh-5AS: 63 sh-6A: 64 sh-6AS: 65 sh-7A: 66 sh-7AS: 67 sh-8A: 68 sh-8AS: 69 sh-9A: 70 sh-9AS: 71 sh-10A: 72 sh-10AS: 73 sh-11A: 74 sh-11AS: 75 sh-12A: 76 sh-12AS: 77 sh-13A: 78 sh-13AS: 79 sh-14A: 80 sh-14AS: 81 sh-15A: 82 sh-15AS: 83 sh-16A: 84 sh-16AS: 85 sh-17A: 86 sh-17AS: 87 sh-18A: 88 sh-18AS: 89 sh-19A: 90 sh-19AS: 91 sh-20A: 92 sh-20AS: 93 sh-21A: 94 sh-21AS:
  8. The use of claim 1, wherein the pharmaceutical composition further comprises a second therapeutically active component that is an immune checkpoint inhibitor.
  9. A pharmaceutical combination comprising: (1) a first therapeutically active component that is a TDG inhibitor; (2) a second therapeutically active component that is an immune checkpoint inhibitor.
  10. An sgRNA targeting the human TDG sequence for use in CRISPR-Cas9 gene knockout technology, wherein the sgRNA is selected from the group consisting of (each presented 5' to 3'): 1 sg-1: GCTATAAAACTGGAAGTTAG 2 sg-2: TGTATTTCAGAGGCTCCAAA 3 sg-3: ACGAAATATGGACGTTCAAG 4 sg-4: TGGGTCATCCACTGCCCATT 5 sg-5: TGGCATAAACCCGGGACTAA 6 sg-6: TTTGACCTACAGCTTGCCCA 7 sg-7: GTTGAGAGCGTGGAGTTAAG 8 sg-8: TGAGGTCCAGCTGAACCATA 9 sg-9: GGGCATCATTACCCTGGACC 10 sg-10: CTACCAGGGAAGTATGGTAT.
  11. An siRNA targeting the human TDG sequence, wherein the siRNA has a sequence selected from the group consisting of (each presented 5' to 3'): 11 si-1S: GAACGAAAUAUGGACGUUCAA 12 si-1AS: UUGAACGUCCAUAUUUCGUUC 13 si-2S: GGACUUAAGAGAUCAGUUGAA 14 si-2AS: UUCAACUGAUCUCUUAAGUCC 15 si-3A: GGUUAUGAGGCAGCAUAUGGU 16 si-3AS: ACCAUAUGCUGCCUCAUAACC 17 si-4A: CAGCUAUUCCCUUCAGCAA 18 si-4AS: UUGCUGAAGGGAAUAGCUG 19 si-5A: CCAGAACAACAGAACCAAA 20 si-5AS: UUUGGUUCUGUUGUUCUGG 21 si-6A: GGAUGAUCACACUCUACCA 22 si-6AS: UGGUAGAGUGUGAUCAUCC 23 si-7A: GCAAAGAUCUCUCCAGUAA 24 si-7AS: UUACUGGAGAGAUCUUUGC 25 si-8A: GAAGGAGGACGUAUUCUAGUA 26 si-8AS: UACUAGAAUACGUCCUCCUUC 27 si-9A: GACGUAUUCUAGUACAGAA 28 si-9AS: UUCUGUACUAGAAUACGUC 29 si-10A: CACGAAUAGCAGUGUUUAA 30 si-10AS: UUAAACACUGCUAUUCGUG 31 si-11A: GAAACUCUCUGCUAUGUUA 32 si-11AS: UAACAUAGCAGAGAGUUUC 33 si-12A: GACAAAGUUCAUUACUACA 34 si-12AS: UGUAGUAAUGAACUUUGUC 35 si-13A: GAAGGACUUAAGAGAUCAGUU 36 si-13AS: AACUGAUCUCUUAAGUCCUUC 37 si-14A: GACUUAAGAGAUCAGUUGA 38 si-14AS: UCAACUGAUCUCUUAAGUC 39 si-15A: GAAAGGCAUUGAACGAAAUAU 40 si-15AS: AUAUUUCGUUCAAUGCCUUUC 41 si-16A: GGACGUUCAAGAGGUGCAA 42 si-16AS: UUGCACCUCUUGAACGUCC 43 si-17A: GUUCAAGAGGUGCAAUAUA 44 si-17AS: UAUAUUGCACCUCUUGAAC 45 si-18A: GCAAUAUACAUUUGACCUA 46 si-18AS: UAGGUCAAAUGUAUAUUGC 47 si-19A: GGUGGUGCUUACGGAGAAA 48 si-19AS: UUUCUCCGUAAGCACCACC 49 si-20A: GGAGUUAAGAGGAGAAUCA 50 si-20AS: UGAUUCUCCUCUUAACUCC 51 si-21A: GACCAAAUUCCUUCCUUUA 52 si-21AS: UAAAGGAAGGAAUUUGGUC; in the above nucleic acid sequences, U nucleotides and T nucleotides are interchangeable.
  12. An shRNA targeting the human TDG sequence, wherein the shRNA has a sequence selected from the group consisting of (each presented 5' to 3'): 53 sh-1A: 54 sh-1AS: 55 sh-2A: 56 sh-2AS: 57 sh-3A: 58 sh-3AS: 59 sh-4A: 60 sh-4AS: 61 sh-5A: 62 sh-5AS: 63 sh-6A: 64 sh-6AS: 65 sh-7A: 66 sh-7AS: 67 sh-8A: 68 sh-8AS: 69 sh-9A: 70 sh-9AS: 71 sh-10A: 72 sh-10AS: 73 sh-11A: 74 sh-11AS: 75 sh-12A: 76 sh-12AS: 77 sh-13A: 78 sh-13AS: 79 sh-14A: 80 sh-14AS: 81 sh-15A: 82 sh-15AS: 83 sh-16A: 84 sh-16AS: 85 sh-17A: 86 sh-17AS: 87 sh-18A: 88 sh-18AS: 89 sh-19A: 90 sh-19AS: 91 sh-20A: 92 sh-20AS: 93 sh-21A: 94 sh-21AS:
  13. An sgRNA sequence for constructing a Trp53 knockout mouse model, wherein the sequence (5 '-3') comprises: 95 mTrp53_sg-1: AGTGAAGCCCTCCGAGTGTC; 96 mTrp53_sg-2: GACCCTGTCACCGAGACCCC.
  14. An sgRNA sequence for constructing a Tdg knockout mouse model, wherein the sequence comprises: 97 mTdg_sg-1: TTCTAGATTGGCATTAACCC; 98 mTdg_sg-2: CCGGGAAGGAGGGCGCATCC.

Description

TECHNICAL FIELD The present invention relates to the field of medicine, specifically, the present invention discloses a drug for treating tumor having TP53 gene mutation. BACKGROUND The accumulation of genetic and epigenetic changes in cells can lead to uncontrolled growth and proliferation, which in turn can trigger cancer. TP53 is one of the most common mutant genes in human cancer, and TP53 gene mutation occurs in approximately 50% of human cancers, comprising lung cancer, breast cancer, colon cancer, ovarian cancer and gastric cancer. TP53 mutation can occur at any stage of cancer development and is associated with poor prognosis and resistance to treatment. TP53 is an important tumor suppressor gene that regulates the expression of genes related to cell cycle, DNA repair, and apoptosis as a transcription factor. Its mutation can lead to the loss of related protein function, resulting in the inability to induce cell apoptosis or arrest cell cycle in response to DNA damage, ultimately promoting tumor growth and metastasis. TP53 mutation can also lead to abnormal protein function, thereby promoting tumor growth and metastasis. Although TP53 mutation is important in cancer development and progression, there are currently no drugs that directly target TP53 mutation. There are several challenges in developing direct targeted therapy for TP53, mainly reflected in the following aspects: (1) TP53 is a complex protein with multiple functions, making it difficult to develop drugs that selectively target mutant protein forms without affecting normal protein forms; (2) TP53 mutation can occur at any stage of cancer development, making it difficult to develop drugs that are effective for all stages of cancer; (3) TP53 mutation can be heterozygous or homozygous, resulting in different levels of protein expression and function, and this heterogeneity may make it difficult to develop effective drugs for all TP53 mutant tumors. Although TP53 is a difficult target to drug, its genetic mutations not only cause it to lose normal function, but also activate cascade signaling pathways to promote tumor progression and compensate for the loss of function, suggesting that there may be a large number of "synthetic lethal" partners hidden in these altered pathways. In summary, there is still a need to develop tumor therapeutic drugs targeting TP53 in this field. SUMMARY OF THE INVENTION The inventor has found through research that thymine DNA glycosylation enzyme (TDG for short, the same below) is a good "synthetic lethal" partner for TP53 gene mutations, and has great potential in the treatment of TP53 mutant tumors. The use of a pharmaceutical composition that comprises thymidine DNA glycosylation enzyme (TDG) inhibitors and pharmaceutically acceptable excipients thereof can effectively inhibit the expression of human TDG protein and have a good therapeutic effect on tumors having TP53 gene mutations. In the first aspect of the present invention, it provides a use of a TDG inhibitor for the preparation of a pharmaceutical composition for the treatment of tumors associated with TP53 gene mutations; wherein the pharmaceutical composition comprises a therapeutically effective amount of the TDG inhibitor and pharmaceutically acceptable excipients thereof. In another preferred embodiment, the pharmaceutical composition is used to downregulate the expression level or expression amount of the TP53 gene in a subject. In another preferred embodiment, the tumors associated with TP53 gene mutations are selected from the group consisting of: lung cancer, skin melanoma, liver cancer, breast cancer, acute myeloid leukemia, colon cancer, colorectal cancer, esophageal cancer, gastric cancer, pancreatic cancer, and bladder cancer. In another preferred embodiment, the TP53 gene mutations are selected from the group consisting of: missense mutation, gene deletion, frameshift mutation, splice site mutation, and truncation mutation. In another preferred embodiment, the protein sequence changes caused by TP53 gene mutations include but are not limited to the following groups: p.146_149WVDS>C, p.157_158insL, p.165_166insYKQ, p.173_174VR>G, p.239_240insN, p.247_248NR>KW, p.249_250insR, p.A119fs, p.A138P, p.A159D, p.A159P, p.A159V, p.A161D, p.A161T, p.A189A, p.A347P, p.A347V, p.A70A, p.A74S, p.A76fs, p.A88fs, p.C124*, p.C124R, p.C135F, p.C135fs, p.C135R, p.C135Y, p.C141W, p.C141Y, p.C176F, p.C176fs, p.C176S, p.C176W, p.C176Y, p.C229fs, p.C238F, p.C238fs, p.C238G, p.C238R, p.C238S, p.C238Y, p.C242F, p.C242fs, p.C242G, p.C242R, p.C242S, p.C242W, p.C242Y, p.C275F, p.C275fs, p.C275G, p.C275Y, p.C277F, p.D148G, p.D207Y, p.D228fs, p.D259V, p.D259Y, p.D281G, p.D281N, p.D281Y, p.D48fs, p.D48N, p.D49H, p.E11Q, p.E171*, p.E171del, p.E180*, p.E180fs, p.E204*, p.E204fs, p.E224D, p.E224E, p.E224K, p.E258*, p.E258A, p.E258K, p.E271*, p.E271fs, p.E271K, p.E285K, p.E285V, p.E286K, p.E287*, p.E287D, p.E294*, p.E294fs, p.E298*, p.E326*, p.E326K, p.E336*, p.E336fs, p.E33