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CN-121974980-A - Polypeptide capable of selectively inhibiting ZDHC 1-p53C135 interaction and application thereof

CN121974980ACN 121974980 ACN121974980 ACN 121974980ACN-121974980-A

Abstract

The invention provides a polypeptide capable of selectively inhibiting the interaction of ZDHC 1-p53C135, which comprises a core sequence of SEQ ID No.1: NKMFCQLAK, can selectively inhibit the interaction of ZDHC 1-p53C135, promote the degradation of mutant p53, inhibit the growth of various tumor cells, has the characteristics of high specificity, low toxic and side effects, broad-spectrum anti-tumor activity and the like, provides a new drug candidate for the clinical treatment of p53 mutant tumors, and provides an important reference for the clinical treatment of p53 mutant tumors.

Inventors

  • XIANG TINGXIU
  • LI RENYAN
  • RONG HUAN
  • XU RUQING
  • Pang Huayang

Assignees

  • 重庆大学附属肿瘤医院
  • 重庆摩斯码可生物科技有限公司

Dates

Publication Date
20260505
Application Date
20251230

Claims (7)

  1. 1. A polypeptide that selectively inhibits the zdhc 1-p53C135 interaction, wherein said polypeptide comprises the core sequence of SEQ ID No.1: NKMFCQLAK.
  2. 2. The polypeptide of claim 1, wherein the amino acid sequence of the polypeptide is one of: (1)SEQ ID No.2:RRRRRRRR-NKMFCQLAK-NH 2 ; (2) SEQ ID No.3 Ac-NKMFCQLAK-Ahx-RRRRRRRR-NH 2 , wherein Ac is N-terminal acetyl modification, ahx is 6-aminocaproic acid connecting arm, -NH 2 is C-terminal amino modification.
  3. 3. Use of a polypeptide according to any one of claims 1 to 2 for the preparation of a medicament for the treatment of a tumor, wherein the tumor is a p53 mutation-related tumor.
  4. 4. The use according to claim 3, wherein the p53 mutation-associated tumors include, but are not limited to, human metastatic pancreatic adenocarcinoma, human colorectal adenocarcinoma, human esophageal squamous carcinoma, human breast adenocarcinoma, human pancreatic ductal carcinoma, human renal clear cell adenocarcinoma, human non-small cell lung carcinoma, human hepatocellular carcinoma.
  5. 5. The use according to claim 3, wherein the medicament promotes mutant p53 degradation by inhibiting the interaction of zdhc 1 with p53C135, thereby inhibiting tumor cell proliferation, inducing tumor cell apoptosis, blocking tumor cell cycle, reducing tumor cell migration and invasiveness.
  6. 6. A pharmaceutical composition comprising a therapeutically effective amount of the polypeptide of claim 1 or 2.
  7. 7. The pharmaceutical composition of claim 6, wherein the dosage form of the pharmaceutical composition comprises, but is not limited to, an injection, including, but not limited to, an intravenous injection, a subcutaneous injection, an oral preparation, including, but not limited to, a tablet, a capsule, an oral liquid, or a topical preparation, including, but not limited to, an ointment, a gel.

Description

Polypeptide capable of selectively inhibiting ZDHC 1-p53C135 interaction and application thereof Technical Field The invention relates to the technical field of medicines, in particular to a polypeptide for selectively inhibiting the interaction of ZDHC 1-p53C135 and application thereof. Background TP53 is an important oncogene, and its encoded p53 protein is a transcription factor capable of binding DNA. When a cell is exposed to a stress condition, it plays a key role by precisely regulating mechanisms such as cell growth arrest, induction of senescence, initiation of apoptotic cell death, etc. (Liu Y, et al Cancer cell 2024;42 (6): 946-967.). The function is mainly achieved by transcriptional regulation of multiple target genes, including p21, which blocks cell cycle progression, and Bax and Puma genes, which promote apoptosis. In the early stages of tumorigenesis, the stress response triggered by oncogene activation or cell cycle regulation disorders is one of the prominent features of tumor evolution. At this point, DNA replication errors caused by oncogenic factors trigger a series of cascades involving ATM, chk1, chk2 kinase and p53 activation, which in turn induce senescence or apoptosis programs （Dsouza R, et al. Mol Biol Rep. 2025;52 (1):333; Li Q, et al. Signal Transduct Target Ther. 2023;8 (1):338.）,, and this p 53-dependent response mechanism is the central defense line for the body to clear primary tumor cells or damaged cells, maintaining genome stability. The study data show that TP53 gene mutations (Khan AA, et al CANCER METASTASIS Rev.2021; 40 (1): 245-272.) are present in nearly 50% of human cancer cases, of which about 90% are of the missense mutation type, resulting in the production of an abnormal p53 protein carrying a single point mutation. From a protein structural standpoint, about 28% of the high frequency mutation sites (e.g., R175, G245, R248, R249, R273, R282) are concentrated in the DNA Binding Domain (DBD) of p53, and these mutations result in an adaptive change in protein structure (Voskarides K, et al cells 2023;12 (3): 512). Functionally, mutant p53 may exhibit a loss of transcriptional activity and tumor suppressor function (LOF) inherent to wild-type p53, and may interfere with and suppress normal function of wild-type p53 via the "dominant negative effect" (dominant negative). Further complicating matters, some mutants p53 even acquire entirely new biological functions of the tumor promotion, namely "gain-of-function, GOF" (Peuget S, et al Nat Rev cancer 2024; 24 (3): 192-215). By means of GOF effect, mutant p53 is able to regulate the development and progression of tumors in multiple dimensions, promote immune escape, enhance Cancer cell stem properties, etc. (Song H, et al Cancer discover.2024; 14 (11): 2055-2060.). Experimental animal models have also further demonstrated that mice bearing mutant p53 exhibit a more aggressive tumor phenotype and a higher propensity to metastasize (Wang Z, et al. Cancer Discov. 2024;14(2):362-379; Lane D,et al. Cancer Discov. 2024;14(2):211 -213). than p 53-deleted or wild-type mice and, therefore, p53 is considered a very potential target in the field of cancer therapy. For the problem of p53 wild-type loss of function, there are mainly several strategies, namely, restoring its trans-transcriptional activation function by introducing the complete p53 gene instead of the mutant gene. Such as recombinant adenovirus vector-mediated wild-type p53 expression system (rAD 5-p 53), under the trade name GENDICINETM, and was approved by the national drug administration (CFDA) for the treatment of head and neck malignancies in 2003. Another similar adenovirus vector, ad-p53, is currently being developed for clinical trials against recurrent or metastatic head and neck cancer (NCT 03544723). However, it is common for the tumor to recur after treatment because of the difficulty in achieving efficient transduction of all tumor cells by the viral vector. And secondly, targeting the interference p53-MDM2/MDM4 complex and changing mutant p53 conformation by using small molecules. Inhibition of MDM and MDMX is therefore also considered a key target for cancer treatment. The first type of MDM2 inhibitor, nutlin 3a, was developed by Roche, and it, by binding to MDM2, blocks the interaction of p53 with MDM2, promotes the accumulation of p53 and enhances its transcriptional activity. Currently, nutlin 3a has been demonstrated to induce cancer cells in vitro, cycle arrest and apoptosis in vivo. Based on this, the rogowski company further developed RG7112 (RO 5045337) and RG7388 (RO 5503781). In addition, other companies and institutions have developed MDM2 inhibitors such as AMG232 from Kartos, SAR405838 from Sainophenanthrene (MI-77301), and Merck MK-8242 (SCH-900242), among others. However, the clinical study stage was significantly hemopoxic. Aiming at the problem of mutant p53, there are mainly several strategies, namely, the anti-tumor purpose is achi