Polypeptide compound, pharmaceutical composition and application

Abstract

The invention provides a polypeptide compound, a pharmaceutical composition and application, and belongs to the technical field of medicines. The invention provides a polypeptide compound or a pharmaceutically acceptable salt thereof. The polypeptide compound has an amino acid sequence as shown in a formula I in the specification. The polypeptide compound provided by the invention has remarkable DLL3 targeting affinity. Formula I: X1-X2-[Ci-X3-Gly-X4-X5-X6-X7-Trp-Thr-Cii]-X8-Trp is shown in the description.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a polypeptide compound, a pharmaceutical composition and an application thereof. Background Art

[0002] DLL3 (Delta-like canonical Notch ligand 3) is a member of the Notch pathway ligand family and plays a key role in Notch signaling. DLL3 is a single-pass transmembrane protein attached to the cell surface, consisting of 619 amino acids, including 1 DSL domain, 1 intracellular domain and 6 epidermal growth factor-like domains. Studies have found that DLL3 is a highly tumor-selective cell surface target, such as being expressed in neural or neuroendocrine tumors, so targeting DLL3 to treat related diseases such as tumors has become a hot topic in current research and development. Summary of the invention

[0003] The purpose of the present invention is to provide a polypeptide compound, a pharmaceutical composition and an application. The polypeptide compound provided by the present invention has significant DLL3 targeting affinity.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The present invention provides a polypeptide compound or a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has an amino acid sequence shown in Formula I:

[0006] X1-X2-[Ci-X3-Gly-X4-X5-X6-X7-Trp-Thr-Cii]-X8-Trp Formula I;

[0007] In the formula I, Ci and Cii are independently selected from cysteine ​​(Cys), homocysteine ​​(Hys) or 2,2-2-methylcysteine ​​(Pen), and "[]" indicates that Ci and Cii are cyclized through their respective -S- to -SS- bonds;

[0008] X1 is selected from tryptophan (Trp) or leucine (Leu);

[0009] X2 is selected from aspartic acid (Asp), 1-aminocyclopropanecarboxylic acid (AC3C), (2S)-2-amino-4,4-difluorobutyric acid (dFAbu), L-4-methoxyphenylalanine (Phe(4-OMe)), 1-naphthyl-L-alanine (1-Nal), L-4-phenylphenylalanine (Phe(4-Ph)), 3-(3-pyridyl)-D-alanine (3Pya), 3-morpholino-L-alanine (Amp) or L-cyclopropylalanine (Cpa);

[0010] X3 is selected from tryptophan (Trp), L-4-phenylphenylalanine (Phe(4-Ph)), 3-(3-pyridyl)-D-alanine (3Pya), L-4-methoxyphenylalanine (Phe(4-OMe)), 1-naphthyl-L-alanine (1-Nal), cyclobutyl-L-glycine (AC4C), cyclopropyl-L-glycine (AC3C), 3-cyclohexyl-L-alanine (Cha), L-3,4-difluorophenylalanine (Phe(3,4-2F)), 3-morpholino-L-alanine (Amp), L-cyclobutylalanine (Cba) or L-cyclopropylalanine (Cpa);

[0011] X4 is selected from asparagine (Asn) or aspartic acid (Asp);

[0012] X5 is selected from threonine (Thr) or asparagine (Asn);

[0013] X6 is selected from aspartic acid (Asp) or serine (Ser);

[0014] X7 is selected from aspartic acid (Asp) or glutamic acid (Glu);

[0015] X8 is selected from threonine (Thr) or valine (Val).

[0016] Preferably, Ci and Cii are independently selected from cysteine ​​or 2,2-2-methylcysteine.

[0017] Preferably, the polypeptide compound has any one of the following amino acid sequences: Trp-Asp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Asp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0018] Trp-AC3C-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0019] Trp-dFAbu-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0020] Trp-Phe(4-OMe)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-1-Nal-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0021] Trp-Asp-[Cys-(Phe(4-Ph)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0022] Trp-Asp-[Cys-3Pya-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Asp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Asp-[Cys-1-Nal-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0023] Trp-Amp-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-3Pya-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0024] Trp-Cpa-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-(Phe(4-Ph)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0025] Trp-(Phe(4-Ph)-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Amp-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Amp-[Cys-Phe(3,4-2F)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Amp-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0026] Trp-Amp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0027] Trp-1-Nal-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0028] Trp-1-Nal-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0029] Trp-Amp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0030] Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-1-Nal-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0031] Trp-1-Nal-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0032] Trp-1-Nal-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0033] Trp-Amp-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0034] Trp-1-Nal-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0035] Trp-Amp-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0036] Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Pen]-Thr-Trp;

[0037] Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0038] Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp; Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp;

[0039] Trp-Amp-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp;

[0040] Trp-1-Nal-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp;

[0041] Trp-Amp-[Cys-Tyr(4-AE)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp.

[0042] Preferably, the N-terminal end-capping method of the polypeptide compound is acetylation end-capping, and the C-terminal end-capping method is amidation end-capping.

[0043] Preferably, it is characterized in that the polypeptide compound is any one of the following compounds: Ac-Trp-Asp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0044] Ac-Trp-AC3C-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0045] Ac-Trp-dFAbu-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0046] Ac-Trp-Phe(4-OMe)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-Trp-Gly-Asn-Thr -Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-(Phe(4-Ph)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0047] Ac-Trp-Asp-[Cys-3Pya-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-Phe(4-OMe)-Gly-Asn-T hr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-1-Nal-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0048] Ac-Trp-Amp-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-3Pya-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0049] Ac-Trp-Cpa-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-(Phe(4-Ph)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0050] Ac-Trp-(Phe(4-Ph)-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-Phe(3,4-2F)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0051] Ac-Trp-Amp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0052] Ac-Trp-1-Nal-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0053] Ac-Trp-1-Nal-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0054] Ac-Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-1-Nal-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-1-Nal-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-1-Nal-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0055] Ac-Trp-Amp-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-1-Nal-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0056] Ac-Trp-Amp-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Pen]-Thr-Trp-NH2;

[0057] Ac-Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;

[0058] Ac-Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2;Ac-Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2;Ac-Trp-Amp-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2;Ac-Trp-1-Nal-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2。

[0059] Ac-Trp-Amp-[Cys-Tyr(4-AE)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2.

[0060] The present invention provides a pharmaceutical composition, comprising one or more of the polypeptide compounds and pharmaceutically acceptable salts thereof described in the above technical solution.

[0061] The present invention provides the use of the polypeptide compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition described in the above technical solution in the preparation of diagnostic reagents, drug carriers or therapeutic drugs for diseases related to the DLL3 target.

[0062] Preferably, the disease associated with the DLL3 target is a tumor.

[0063] Preferably, the tumor is selected from lung cancer, brain cancer, central nervous system cancer, neuroendocrine tumors, head and neck cancer, esophageal cancer, malignant pleural mesothelioma, breast cancer, liver cancer, hepatobiliary cancer, pancreatic cancer, gastric cancer, gastrointestinal cancer, intestinal cancer, kidney cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, adrenal cancer, skin cancer or melanoma.

[0064] Preferably, the lung cancer is small cell lung cancer or large cell lung cancer; the central nervous system cancer is glioma, glioblastoma multiforme or neuroblastoma; the head and neck cancer is head and neck squamous cell carcinoma, pharyngeal cancer, nasopharyngeal carcinoma or thyroid cancer; the breast cancer is triple-negative breast cancer; the intestinal cancer is colorectal cancer; and the renal cancer is clear cell renal cell carcinoma.

[0065] The present invention provides a polypeptide compound or a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has an amino acid sequence shown in Formula I. The polypeptide compound provided by the present invention has significant DLL3 targeting affinity. In the test example of the present invention, the affinity of the polypeptide compound of the present invention to the target protein DLL3 was tested by using biomembrane interference technology. The results showed that the polypeptide compound provided by the present invention has significant targeting affinity to the DLL3 target, and the affinity constant K of most cyclic peptide compounds to the DLL3 target is 1.347. D <100nM, and some cyclic peptide compounds are difficult to dissociate after binding to the DLL3 target (dissociation rate constant koff <10 -2 1 / s), indicating that the peptide compounds provided by the present invention have significant drug development potential on the DLL3 target. DETAILED DESCRIPTION

[0066] The present invention provides a polypeptide compound or a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has an amino acid sequence shown in Formula I:

[0067] X1-X2-[Ci-X3-Gly-X4-X5-X6-X7-Trp-Thr-Cii]-X8-Trp Formula I;

[0068] In the formula I, Ci and Cii are independently selected from cysteine ​​(Cys), homocysteine ​​(Hcys) or 2,2-2-methylcysteine ​​(Pen), and "[]" indicates that Ci and Cii are cyclized through their respective -S- to achieve -SS- bonds;

[0069] X1 is selected from tryptophan (Trp) or leucine (Leu);

[0070] X2 is selected from aspartic acid (Asp), 1-aminocyclopropanecarboxylic acid (AC3C), (2S)-2-amino-4,4-difluorobutyric acid (dFAbu), L-4-methoxyphenylalanine (Phe(4-OMe)), 1-naphthyl-L-alanine (1-Nal), L-4-phenylphenylalanine (Phe(4-Ph)), 3-(3-pyridyl)-D-alanine (3Pya), 3-morpholino-L-alanine (Amp) or L-cyclopropylalanine (Cpa);

[0071] X3 is selected from tryptophan (Trp), L-4-phenylphenylalanine (Phe(4-Ph)), 3-(3-pyridyl)-D-alanine (3Pya), L-4-methoxyphenylalanine (Phe(4-OMe)), 1-naphthyl-L-alanine (1-Nal), cyclobutyl-L-glycine (AC4C), cyclopropyl-L-glycine (AC3C), 3-cyclohexyl-L-alanine (Cha), L-3,4-difluorophenylalanine (Phe(3,4-2F)), 3-morpholino-L-alanine (Amp), L-cyclobutylalanine (Cba) or L-cyclopropylalanine (Cpa);

[0072] X4 is selected from asparagine (Asn) or aspartic acid (Asp);

[0073] X5 is selected from threonine (Thr) or asparagine (Asn);

[0074] X6 selects aspartic acid (Asp) or serine (Ser);

[0075] X7 is selected from aspartic acid (Asp) or glutamic acid (Glu);

[0076] X8 is selected from threonine (Thr) or valine (Val).

[0077] As an embodiment of the present invention, Ci and Cii are independently selected from cysteine ​​or 2,2-2-methylcysteine.

[0078] As an embodiment of the present invention, the polypeptide compound has any one of the following amino acid sequences:

[0079] Trp-Asp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0080] Trp-Asp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0081] Trp-AC3C-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0082] Trp-dFAbu-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0083] Trp-Phe(4-OMe)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0084] Trp-1-Nal-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0085] Trp-Asp-[Cys-(Phe(4-Ph)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0086] Trp-Asp-[Cys-3Pya-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0087] Trp-Asp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0088] Trp-Asp-[Cys-1-Nal-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0089] Trp-Amp-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0090] Trp-3Pya-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0091] Trp-Cpa-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0092] Trp-(Phe(4-Ph)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0093] Trp-(Phe(4-Ph)-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0094] Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0095] Trp-Amp-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0096] Trp-Amp-[Cys-Phe(3,4-2F)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0097] Trp-Amp-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0098] Trp-Amp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0099] Trp-1-Nal-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0100] Trp-1-Nal-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0101] Trp-Amp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0102] Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0103] Trp-1-Nal-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0104] Trp-1-Nal-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0105] Trp-1-Nal-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0106] Trp-Amp-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0107] Trp-1-Nal-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0108] Trp-Amp-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0109] Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Pen]-Thr-Trp;

[0110] Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;

[0111] Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp;

[0112] Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp;

[0113] Trp-Amp-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp; Trp-1-Nal-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp.

[0114] Trp-Amp-[Cys-Tyr(4-AE)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp.

[0115] As an embodiment of the present invention, the N-terminal of the peptide compound is capped by acetylation (eg, the N-terminal can be capped by acetamide), and the C-terminal is capped by amidation.

[0116] As an embodiment of the present invention, the polypeptide compound is any one of the compounds in Table 1:

[0117] Table 1 Types of polypeptide compounds

[0118]

[0119]

[0120] The present invention provides a method for preparing the polypeptide compound described in the above technical solution, comprising the following steps:

[0121] According to the amino acid sequence of the polypeptide compound described in the above technical solution, a peptide sequence is prepared on a resin to obtain a peptide resin;

[0122] Using a cleavage solution to cleave the peptide resin to obtain a crude peptide;

[0123] The crude peptide is subjected to a disulfide bond cyclization reaction to obtain the polypeptide compound.

[0124] According to the amino acid sequence of the polypeptide compound described in the above technical solution, the present invention prepares a peptide sequence on a resin to obtain a peptide resin. The resin used in the embodiment of the present invention may be MBHA Resin, and the MBHA Resin may be swollen and Fmoc protective group removed in sequence before use. In the embodiment of the present invention, the swelling reagent may be dichloromethane; washing may be performed after swelling, and the washing reagent may be N, N-dimethylformamide. In the embodiment of the present invention, the reagent used for removing the Fmoc protective group may be a N, N-dimethylformamide solution of piperidine, wherein the volume ratio of piperidine to N, N-dimethylformamide may be 1:4; the removal of the Fmoc protective group may include sequentially performing a first stage reaction and a second stage reaction; the temperature of the first stage reaction may be room temperature, and the time may be 5 minutes; the temperature of the second stage reaction may be room temperature, and the time may be 10 minutes.

[0125] The present invention does not specifically limit the specific method for preparing the peptide sequence on the resin, and a method well known to those skilled in the art can be used. In the embodiment of the present invention, specifically, according to the amino acid sequence of the polypeptide compound, the Fmoc-protected amino acids are sequentially coupled to the resin, and then the Fmoc protecting group is removed, and finally the end is capped to obtain the peptide resin.

[0126] In the embodiment of the present invention, specifically, the Fmoc-protected amino acid, 2-(1H-benzotriazolyl L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, N,N-diisopropylethylamine and N,N-dimethylformamide are mixed for activation; then the obtained activation solution is mixed with the resin from which the Fmoc protecting group is removed for coupling reaction, and then the above operation is repeated to sequentially couple other Fmoc-protected amino acids. In the embodiment of the present invention, the activation can be carried out under ice bath conditions, and the activation time can be 10 minutes; the coupling reaction can be carried out under room temperature conditions, and the coupling reaction time can be 1 hour.

[0127] In the embodiment of the present invention, the operation of removing the Fmoc protecting group after coupling the Fmoc-protected amino acid can be performed with reference to the above technical scheme, which will not be described in detail here.

[0128] In an embodiment of the present invention, the end-capping reagents may be Ac2O and N,N-diisopropylethylamine, and the end-capping may be washed and dried in sequence to obtain the peptide resin. The present invention does not specifically limit the specific conditions of the end-capping, washing and drying, and the conditions familiar to those skilled in the art may be used.

[0129] After obtaining the peptide resin, the present invention uses a cleavage solution to cleave the peptide resin to obtain a crude peptide. In an embodiment of the present invention, the cleavage solution may include trifluoroacetic acid (TFA), triisopropylsilane (TIS), water and 1,8-octanedithiol (EDT), and the volume ratio of TFA, TIS, H2O and EDT may be 92.4:2.5:2.5:2.5. In the embodiment of the present invention, the cleavage is carried out in the presence of tris(2-carbonylethyl)phosphine hydrochloride (TCEP), and the concentration of TCEP in the system during the cleavage may be 1 mg / mL; the cleavage may be carried out at room temperature, and the cleavage time may be 2h. In an embodiment of the present invention, the cleavage may further include: filtering the obtained cleavage liquid, collecting the filter cake and washing it with the cleavage solution, adding methyl tert-butyl ether dropwise to the combined filtrate, centrifuging after sedimentation under ice bath conditions, collecting the solid and washing it with methyl tert-butyl ether, and then drying to obtain the crude peptide.

[0130] After obtaining the crude peptide, the present invention performs a disulfide bond cyclization reaction on the crude peptide to obtain the polypeptide compound. The disulfide bond cyclization reaction in the embodiment of the present invention can be performed in the presence of a buffer, ACN and dimethyl sulfoxide; the volume ratio of the buffer, ACN and dimethyl sulfoxide can be 52:52:5.5; the buffer can be prepared by: dissolving 4g NH4OA in 1L H2O, and then adjusting the pH to 9 with ammonia water; the disulfide bond cyclization reaction can be performed at room temperature, and the disulfide bond cyclization reaction time can be 2h. In the embodiment of the present invention, the disulfide bond cyclization reaction can also include: purifying the obtained product system by Pre-HPLC to obtain a purified solution, concentrating and freeze-drying to obtain the polypeptide compound.

[0131] The present invention provides a pharmaceutical composition, comprising one or more of the polypeptide compounds and pharmaceutically acceptable salts thereof described in the above technical solution. In an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, and the present invention has no special limitation on the pharmaceutically acceptable excipient, and any pharmaceutically acceptable excipient well known to those skilled in the art can be used.

[0132] The present invention provides the use of the polypeptide compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition described in the above technical solution in the preparation of diagnostic reagents, drug carriers or therapeutic drugs for diseases related to the DLL3 target.

[0133] At present, the global DLL3 pipeline has a low concentration and is in an early stage of clinical development (1 project in Phase III, 4 projects in Phase I). The main indications for development are small cell lung cancer (SCLC), and the drug forms are ADC, bispecific antibodies / polyspecific antibodies, and CAR-T. The clinical effect of Rova-T in Phase III is currently not as good as expected, and BMS directly announced that the drug has failed to treat small cell lung cancer. The remaining global pipelines are three antibody projects in Phase I and one CAR-T project in Phase I: the three antibody projects involved, namely Amgen's AMG757, Harpoon's HPN328, and BI's BI764532, all specifically target cancer cells with high DLL3 expression by activating T cells with CD3, and have shown good anti-tumor activity in both preclinical and clinical stages.

[0134] In summary, the current drug development for DLL3 target is still in the early stage, the number of candidate drugs is small, and the indications are mostly concentrated in SCLC, a tumor field with large unmet needs. SCLC accounts for about 15% of lung cancer cases. It proliferates rapidly and is prone to extensive metastasis in the early stage. The 5-year survival rate of most SCLC patients is only 3%. In addition to first-line chemotherapy regimens such as platinum-etoposide, there are almost no other treatment options, and almost all patients will relapse soon after receiving chemotherapy. Therefore, SCLC urgently needs new treatment options. Based on the important role of DLL3 in tumor development and the lag in the current clinical development of this target, finding a ligand that highly specifically targets DLL3, and then using it for the diagnosis and treatment of patients with tumors that overexpress DLL3 will benefit more tumor patients and have important clinical significance and social value. The polypeptide compounds provided by the present invention have significant DLL3 targeting affinity and have significant drug development potential on the DLL3 target.

[0135] In an embodiment of the present invention, the disease associated with the DLL3 target may be a tumor; the tumor may be selected from lung cancer, brain cancer, central nervous system cancer, neuroendocrine tumor, head and neck cancer, esophageal cancer, malignant pleural mesothelioma, breast cancer, liver cancer, hepatobiliary cancer, pancreatic cancer, gastric cancer, gastrointestinal cancer, intestinal cancer, kidney cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, adrenal cancer, skin cancer or melanoma. In an embodiment of the present invention, the lung cancer may be small cell lung cancer or large cell lung cancer; the central nervous system cancer may be glioma, glioblastoma multiforme or neuroblastoma; the head and neck cancer may be head and neck squamous cell carcinoma, pharyngeal cancer, nasopharyngeal cancer or thyroid cancer; the thyroid cancer may specifically be medullary thyroid carcinoma; the breast cancer may be triple negative breast cancer; the intestinal cancer may be colorectal cancer; the kidney cancer may be clear cell renal cell carcinoma.

[0136] In an embodiment of the present invention, the therapeutic drug may include an active ingredient and a pharmaceutically acceptable excipient; the active ingredient is the polypeptide compound described in the above technical solution, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the above technical solution.

[0137] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0138] Example 1

[0139] Preparation of compound HTPM7020-055, the reaction formula is as follows:

[0140]

[0141] The synthesis of the polypeptide compounds in the present invention adopts the standard Fmoc chemical method, which is as follows:

[0142] (1) Swelling: MBHAResin (0.35 g, 0.2 mmol) was placed in a peptide synthesis tube and swelled with dichloromethane (DCM, 15 mL) for 15 min at room temperature. The solvent was drained and the tube was washed three times with N,N-dimethylformamide (DMF, 15 mL) and used directly in the next step.

[0143] (2) Removal of Fmoc protecting group: add piperidine DMF solution (10 mL, piperidine to DMF volume ratio of 1:4) to the Fmoc peptide resin obtained in step (1), react at room temperature for 5 min, drain, add piperidine DMF solution (10 mL, piperidine to DMF volume ratio of 1:4) again, and react at room temperature for 10 min; after the reaction is completed, drain the reaction solution, wash with DMF (10 mL) 6 times, and drain the solvent; take a small amount of resin and heat it with 5 wt% ninhydrin ethanol solution at 110°C for 3 min, the resin turns dark blue, indicating that Fmoc has been removed, and is directly used in the next reaction.

[0144] (3) Coupling: Fmoc-Trp(Boc)-OH (320 mg, 0.6 mmol, 3 eq) and 2-(1H-benzotriazol L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 193 mg, 0.6 mmol, 3 eq) were dissolved in DMF (20 mL). N,N-diisopropylethylamine (DIEA, 0.208 mL, 1.2 mmol, 6 eq) was added to the resulting reaction solution under ice bath conditions and stirred for activation for 10 min. The resulting activated solution was added to the Fmoc-free resin obtained in step (2) and reacted at room temperature for 1 h. A small amount of the resin was heated with a 5 wt % ninhydrin ethanol solution at 110° C. for 3 min, and the resin became colorless. The reaction solution was drained and washed three times with DMF (10 mL) and directly used in the next reaction.

[0145] (4) Coupling cycle: Repeat the above steps to couple the following amino acids one by one:

[0146] Fmoc-Thr(tBu)-OH (0.24g, 0.6mmol, 3eq);

[0147] Fmoc-Cys(Trt)-OH (0.36g, 0.6mmol, 3eq);

[0148] Fmoc-Thr(tBu)-OH (0.24g, 0.6mmol, 3eq);

[0149] Fmoc-Trp(Boc)-OH (0.32g, 0.6mmol, 3eq);

[0150] Fmoc-Asp(OtBu)-OH (0.25g, 0.6mmol, 3eq);

[0151] Fmoc-Asp(OtBu)-OH (0.25g, 0.6mmol, 3eq);

[0152] Fmoc-Thr(tBu)-OH (0.24g, 0.6mmol, 3eq);

[0153] Fmoc-Asn(Trt)-OH (0.36g, 0.6mmol, 3eq);

[0154] Fmoc-Gly-OH (0.18g, 0.6mmol, 3eq);

[0155] Fmoc-AC4C-OH (0.21g, 0.6mmol, 3eq);

[0156] Fmoc-Cys(Trt)-OH (0.36g, 0.6mmol, 3eq);

[0157] Fmoc-Asp(OtBu)-OH (0.25g, 0.6mmol, 3eq);

[0158] Fmoc-Trp(Boc)-OH (0.32g, 0.6mmol, 3eq);

[0159] After all amino acid couplings are completed, the Fmoc protecting group is removed using the above-mentioned operation;

[0160] Then, Ac2O (56 μL, 0.6 mmol, 3.0 eq) and DIEA (209 μL, 1.2 mmol, 6.0 eq) were added for end-capping, and the mixture was washed alternately with DCM and EtOH for 3 times, with the volume of DCM and EtOH used for each washing being 10 mL respectively. The mixture was drained and transferred to a vacuum oven, and dried in vacuum at 35°C for 2 h to obtain 0.92 g of Ac-Trp(Boc)-Asp(OtBu)-Cys(Trt)-AC4C-Gly-Asn(Trt)-Thr(tBu)-Asp(OtBu)-Asp(Ot Bu)-Trp(Boc)-Thr(tBu)-Cys(Trt)-Thr(tBu)-Trp(Boc)-MBHA resin, which was directly used in the next reaction.

[0161] (5) Cracking: Based on 10 mL / g resin, a cracking solution (9 mL) was added to the resin (0.92 g) obtained in step (4). The cracking solution included trifluoroacetic acid (TFA), triisopropylsilane (TIS), water and 1,8-octanedithiol (EDT), wherein the volume ratio of TFA, TIS, H2O and EDT was 92.4:2.5:2.5:2.5), and then tris(2-carbonylethyl)phosphine hydrochloride (TCEP, 9 mg, 1 mg / mL) was added. The mixture was reacted at room temperature for 2 h, filtered, and washed with the cracking solution (1 mL). The combined filtrate was dropwise added with methyl tert-butyl ether (MTBE, 50 mL), and the mixture was precipitated under ice bath for 1 h. The mixture was centrifuged, and the solid was collected and washed three times with methyl tert-butyl ether (40 mL) to obtain a white solid. The white solid was transferred to a vacuum drying oven and vacuum dried at 35°C for 2 h to obtain 110 mg of crude peptide.

[0162] (6) The crude peptide (110 mg) obtained in step (5) was dissolved in 52 mL of buffer (preparation method: 4 g of NH4OAc was dissolved in 1 L of H2O and then adjusted to pH = 9 with aqueous ammonia), and then ACN (52 mL) and dimethyl sulfoxide (DMSO, 5.5 mL) were added. The mixture was stirred at room temperature for 2 h. LC-MS showed that the reaction was complete. The purified solution was purified by Pre-HPLC, concentrated and lyophilized to obtain the target compound HTPM7020-055 as a white solid (15.86 mg). The yield was 14% and the HPLC purity was 95.85%. MS (ESI) m / z: [M+2H] + / 2=870.1.

[0163] Referring to the similar operation method of Example 1, the polypeptide compounds in Table 2 were synthesized by replacing different amino acids.

[0164] Table 2 Types and purity of peptide compounds

[0165]

[0166]

[0167] Test Example 1 Testing the affinity of peptide compounds for DLL3 targets based on in vitro activity assays

[0168] In this field, in vitro affinity is an important evaluation index for determining the effect of a molecule on a target in the early stages of drug development. This test example uses bio-layer interferometry (BLI) technology to test the affinity of the polypeptide compound of the present invention to the target protein DLL3. The specific steps are as follows:

[0169] The experiment was conducted using an Octet R8 device. Biotin-labeled recombinant human DLL3 protein (AcroBiosystems Inc. Catalog No. DL3-H82E4) was prepared with PBST to a concentration of 20 μg / mL and fixed to the SSA sensor. The program added baseline (60 s), loading (600 s), and baseline (60 s).

[0170] The solidified SSA sensor was subjected to a binding reaction with a polypeptide compound. Specifically, the polypeptide compound was prepared into a mother solution with a concentration of 10 mM using DMSO, diluted to an appropriate concentration using PBST, and then diluted to 7 concentrations by 2 times in a gradient manner. The final concentration of DMSO was controlled within 1% to ensure that the amount of DMSO used did not affect the activity of the protein. The mother solutions of polypeptide compounds with different concentrations and PBST were added to a 96-well plate, and the program was set: Baseline (PBST buffer containing DMSO, 60s), Association (PBST buffer containing DMSO + compound, 90s), Dissociation (PBST buffer containing DMSO, 120s). Each sample well was required to undergo an equilibrium binding and dissociation step. At the same time, the above operation was performed with an SSA sensor without solidified protein as a reference non-specific binding signal.

[0171] After the experiment, Octet high-throughput analysis software Octet Analysis Studio (version 12.2.2.26) was used for analysis. The data processing followed the double subtraction principle, that is, the first step was to subtract the nonspecific binding signal between the SSA sensor and the polypeptide compounds, and the second step was to subtract the nonspecific binding signal between the protein and the PBST buffer containing DMSO. After that, kinetic fitting was performed to obtain the affinity constant KD between the polypeptide compounds and the target protein DLL3.

[0172] Table 3 shows the affinity test results of the peptide compounds with the target protein DLL3. It can be seen from Table 3 that the peptide compounds provided by the present invention have significant targeting affinity for the DLL3 target, and the affinity constants K of most cyclic peptide compounds with the DLL3 target are D <100nM, and some cyclic peptide compounds are difficult to dissociate after binding to the DLL3 target (dissociation rate constant koff <10 -2 1 / s).

[0173] Table 3 Affinity test results of peptide compounds and target protein DLL3

[0174]

[0175]

[0176] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A polypeptide compound or a pharmaceutically acceptable salt thereof, wherein the polypeptide compound has an amino acid sequence as shown in Formula I: X1-X2-[Ci-X3-Gly-X4-X5-X6-X7-Trp-Thr-Cii]-X8-Trp Formula I; In the formula I, Ci and Cii are independently selected from cysteine ​​(Cys), homocysteine ​​(Hys) or 2,2-methylcysteine ​​(Pen), and "[]" indicates that Ci and Cii are cyclized through their respective -S- to -SS- bonds; X1 is selected from tryptophan (Trp) or leucine (Leu); X2 is selected from aspartic acid (Asp), 1-aminocyclopropanecarboxylic acid (AC3C), (2S)-2-amino-4,4-difluorobutyric acid (dFAbu), L-4-methoxyphenylalanine (Phe(4-OMe)), 1-naphthyl-L-alanine (1-Nal), L-4-phenylphenylalanine (Phe(4-Ph)), 3-(3-pyridyl)-D-alanine (3Pya), 3-morpholino-L-alanine (Amp) or L-cyclopropylalanine (Cpa); X3 is selected from tryptophan (Trp), L-4-phenylphenylalanine (Phe(4-Ph)), 3-(3-pyridyl)-D-alanine (3Pya), L-4-methoxyphenylalanine (Phe(4-OMe)), 1-naphthyl-L-alanine (1-Nal), cyclobutyl-L-glycine (AC4C), cyclopropyl-L-glycine (AC3C), 3-cyclohexyl-L-alanine (Cha), L-3,4-difluorophenylalanine (Phe(3,4-2F)), 3-morpholino-L-alanine (Amp), L-cyclobutylalanine (Cba) or L-cyclopropylalanine (Cpa); X4 is selected from asparagine (Asn) or aspartic acid (Asp); X5 is selected from threonine (Thr) or asparagine (Asn); X6 is selected from aspartic acid (Asp) or serine (Ser); X7 is selected from aspartic acid (Asp) or glutamic acid (Glu); X8 is selected from threonine (Thr) or valine (Val).

2. The polypeptide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Said Ci and Cii are independently selected from cysteine ​​or 2,2-2-methylcysteine.

3. The polypeptide compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The polypeptide compound has any one of the following amino acid sequences: Trp-Asp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Asp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-AC3C-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-dFAbu-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Phe(4-OMe)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Asp-[Cys-(Phe(4-Ph)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Asp-[Cys-3Pya-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Asp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp;Trp-Asp-[Cys-1-Nal-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-3Pya-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Cpa-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-(Phe(4-Ph)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-(Phe(4-Ph)-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Phe(3,4-2F)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Pen]-Thr-Trp; Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp; Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp; Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp; Trp-Amp-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp; Trp-1-Nal-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp。 4. The polypeptide compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The N-terminal end-capping method in the polypeptide compound is acetylation end-capping, and the C-terminal end-capping method is amidation end-capping.

5. The polypeptide compound or pharmaceutically acceptable salt thereof according to claim 4, characterized in that: The polypeptide compound is any one of the following compounds: Ac-Trp-Asp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-AC3C-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-dFAbu-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Phe(4-OMe)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-(Phe(4-Ph)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-3Pya-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Asp-[Cys-1-Nal-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-3Pya-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Cpa-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-(Phe(4-Ph)-[Cys-Trp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-(Phe(4-Ph)-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-Phe(3,4-2F)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-Amp-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-Amp-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-Phe(4-OMe)-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2;Ac-Trp-1-Nal-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-Cha-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-AC3C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-Cpa-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Cys-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-Cba-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Pen]-Thr-Trp-NH2; Ac-Trp-1-Nal-[Pen-AC4C-Gly-Asn-Thr-Asp-Asp-Trp-Thr-Cys]-Thr-Trp-NH2; Ac-Trp-Amp-[Cys-Phe(4-OMe)-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2; Ac-Trp-1-Nal-[Cys-Phe(4-OMe)-Gly- Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2; Ac-Trp-Amp-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2; Ac-Trp-1-Nal-[Cys-Cpa-Gly-Asp-Asn-Ser-Glu-Trp-Thr-Cys]-Val-Trp-NH2.

6. A pharmaceutical composition comprising one or more of the polypeptide compound according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof.

7. Use of the polypeptide compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 6 in the preparation of a diagnostic reagent, a drug carrier or a therapeutic drug for a disease associated with the DLL3 target.

8. The use according to claim 7, characterized in that: The disease associated with the DLL3 target is a tumor.

9. The use according to claim 8, characterized in that: The tumor is selected from lung cancer, brain cancer, central nervous system cancer, neuroendocrine tumors, head and neck cancer, esophageal cancer, malignant pleural mesothelioma, breast cancer, liver cancer, hepatobiliary cancer, pancreatic cancer, gastric cancer, gastrointestinal cancer, intestinal cancer, kidney cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, adrenal cancer, skin cancer or melanoma.

10. The use according to claim 9, characterized in that: The lung cancer is small cell lung cancer or large cell lung cancer; the central nervous system cancer is glioma, glioblastoma multiforme or neuroblastoma; the head and neck cancer is head and neck squamous cell carcinoma, pharyngeal cancer, nasopharyngeal carcinoma or thyroid cancer; the breast cancer is triple-negative breast cancer; the intestinal cancer is colorectal cancer; and the kidney cancer is clear cell renal cell carcinoma.

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