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CN-121987812-A - Design method and application of tyrosinase response type medicine for melanoma targeted therapy

CN121987812ACN 121987812 ACN121987812 ACN 121987812ACN-121987812-A

Abstract

The invention discloses a Tyrosinase (TYR) response type drug design method for melanoma targeted therapy and application thereof, belonging to the technical field of biological medicine. The invention is based on biological mechanism of TYR catalytic tyrosine oxidation, combines self-degradation connecting arm drug release strategy, introduces a 3-hydroxy benzyl alcohol-like structure to simulate tyrosine substrate, realizes the specific identification and activation of TYR on the drugs, and is expected to solve the problems of poor targeting and serious adverse reaction of the traditional chemotherapy drugs.

Inventors

  • ZHENG GUOJUN
  • QIU BOXIANG

Assignees

  • 北京化工大学

Dates

Publication Date
20260508
Application Date
20260401

Claims (10)

  1. 1. A Tyrosinase (TYR) response type drug design method for melanoma targeted therapy is characterized by selecting a chemotherapy drug which can be clinically used for cancer therapy, combining a self-degradation connecting arm drug release strategy based on a biological mechanism of TYR catalytic tyrosine oxidation, introducing a 3-hydroxy benzyl alcohol-like structure to simulate a tyrosine substrate, and realizing the specific identification and activation of TYR on the drug, wherein the biological mechanism of TYR catalytic tyrosine oxidation (upper) and the Tyrosinase (TYR) response type drug activation mechanism (lower) are shown in formula 1: , The method comprises the steps of (1), Wherein, the R 1 is optionally substituted mono-, di-or trisubstituted in the phenyl ring; R 1 is hydrogen or a group bonded through a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom; R 2 is optionally substituted; R 2 is hydrogen or a group bonded through a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom; X is a chemical group that is highly related to the structure of a chemotherapeutic agent. X=coo corresponds to carbonate bond coupling, x=conh corresponds to urethane bond coupling, x=co corresponds to ester bond coupling, and X corresponds to ether bond coupling when no X exists.
  2. 2. The agent of claim 1, wherein R 1 is (1) a hydrogen atom, (2) a halogen, (3) a nitro group, (4) a cyano group, (5) an amino group, (6) a hydroxyl group, (7) a sulfonic acid group, (8) a phosphoric acid group, or other groups bonded through a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, or a phosphorus atom.
  3. 3. The medicament of claim 1, wherein R 1 is a single substituent or a combination of substituents as set forth in claim 2.
  4. 4. The agent of claim 1, wherein R 2 is (1) a hydrogen atom, (2) a carboxyl group, (3) an amino group, (4) a propynyl group, (5) a sulfonic acid group, (6) a phosphoric acid group and derivatives thereof, (7) a carboxyl-derived ester or amide bond, (8) an amino-derived amide or carbamate bond, (9) a propynyl-derived triazole group, (10) a sulfonic acid-derived sulfonate bond, (11) a phosphoric acid-derived phosphate bond, and other groups bonded by carbon, nitrogen, oxygen, sulfur, or phosphorus atoms.
  5. 5. A TYR response type drug, X depends on the combination mode of an alcoholic hydroxyl group on a 3-hydroxy-like benzyl alcohol structure and a parent drug, is characterized in that the design method is adopted, and is characterized in that when an active site of the parent drug is the alcoholic hydroxyl group, the coupling mode is carbonate bond coupling, when an active site of the parent drug is amino group, the coupling mode is carbamate bond coupling, when an active site of the parent drug is carboxyl group, the coupling mode is ester bond coupling, and when an active site of the parent drug is phenolic hydroxyl group, the coupling mode is ether bond coupling. Representative is shown in formula 2: , Formula 2.
  6. 6. The TYR-responsive medicament of claim 1, wherein the clinical chemotherapeutic medicament includes, but is not limited to, doxorubicin (Doxorubicin, DOX), gemcitabine (Gemcitabine, GEM), irinotecan (Exatecan, ETC), 7-ethyl-10-hydroxycamptothecin (SN 38), podophyllotoxin (Podophyllotoxin, PTT), paclitaxel (Paclitaxel, PTX), etoposide (Etoposide, ETO), camptothecin (CPT), chlorambucil (Chlorambucil, CB), and the like.
  7. 7. The TYR-responsive drug of claim 1, wherein the self-degradation of the self-degrading linker arm after tyrosinase-catalyzed oxidation of the drug is not limited to the method shown in formula 1, but includes, but is not limited to, other methods of inserting other self-cleaving spacers between the 3-hydroxybenzyl alcohol structure and the drug, typically represented by formula 3: , Formula 3.
  8. 8. The medicament according to claims 1-6, wherein the preferred medicaments are TYR-DOX, TYR-GEM and TYR-ETC, having the structure of formula 4: Formula 4.
  9. 9. Use of a medicament according to any one of claims 1 to 8 for the preparation of a payload of a targeted conjugated medicament such as a polypeptide-drug conjugate and an antibody-drug conjugate for the treatment of melanoma.
  10. 10. Use of a medicament according to any one of claims 1 to 8 for the preparation of a medicament or agent for the treatment of melanoma.

Description

Design method and application of tyrosinase response type medicine for melanoma targeted therapy Technical Field The invention relates to the field of biological medicine, in particular to a tyrosinase response type medicine design method for melanoma targeted therapy, a medicine synthesized according to the method and application thereof, and is particularly suitable for development and clinical transformation of melanoma targeted therapy medicine. Background Skin cancer is one of the most common malignant tumors worldwide, and melanoma accounts for only about 1% of all skin cancer cases, but results in most skin cancer-related deaths [ biochem, biophys, acta gen, subj, 2017, 1861, 256-263 ]. In-situ melanoma can be cured radically after surgical excision and has good prognosis, but once the melanoma is developed into invasive or metastatic lesions, the high invasive biological characteristics of the melanoma lead to limited curative effects of traditional treatment means such as surgery, chemotherapy and radiotherapy, and seriously affect survival prognosis of patients [ Ther, adv. Med. Oncol., 2022, 14, 17588359221134087 ] [ CA Cancer J. Clin., 2020, 70, 78-85 ]. The global Cancer statistics of 2022 show that about 331,647 new cases of global melanoma and 58,645 cases of death are seen, which is a significant challenge in the field of control [ CA Cancer j. Clin, 2024, 74, 229-263 ]. Traditional chemotherapy drugs mostly adopt a systemic administration mode, lack of tumor targeting, are difficult to distinguish normal cells from tumor cells, and are easy to cause serious toxic and side effects. To overcome this bottleneck, the modification of traditional chemotherapeutic drugs into responsive drugs (i.e., inactive drug derivatives that are specifically activated only at the tumor site) has become a very potential tumor targeted therapeutic strategy. Ideally, the responsive drug is activated by specific stimulation signals in the tumor microenvironment (e.g., low pH [ na. Biomed. Eng., 2024, 8, 787-799 ]) high active oxygen levels [ Acta pharm, sin, 2024, 14, 5106-5131.], high Glutathione (GSH) levels [ eur, j. Med. Chem., 2026, 305, 118563.] and overexpressing enzymes [ j. Med. Chem., 2025, 68, 19871-19892.], etc.), thereby achieving specific killing of cancer cells. Among melanomas, tyrosinase (TYR) is very specific for tissue distribution (almost exclusively expressed in melanocytes) and is considered an ideal target for achieving tumor-specific drug activation [ Science, 2023, 381, eade6289 ]. Tyrosinase is a key rate-limiting enzyme in the human melanin synthesis pathway [ int.j. biochem., 1987, 19, 1141-1147 ] [ Nature, 1980, 286, 617-619 ]. The studies demonstrated that tyrosinase expression levels and catalytic activity in melanoma cells were significantly up-regulated compared to normal melanocytes, suggesting an important role in the development of melanoma [ Cancer res., 1987, 47, 3278-3284 ] [ Cancer lett., 1988, 38, 339-346 ]. Tyrosinase can thus act as an ideal endogenous trigger for mediating melanoma-specific drug release. By constructing a tyrosinase-activated drug system, the accurate release of the drug is expected to be realized in the tumor part, and the therapeutic index [ Biomaterials, 2020, 259, 120329 ] [ Nat. Commun., 2025, 16, 6463 ] is remarkably improved. Based on the method, a high-toxicity chemotherapeutic drug which is clinically applied, particularly used for melanoma treatment research is selected, and modification is carried out by relying on a tyrosinase-mediated targeting mechanism, so that the toxic and side effects of the drug on normal cells can be obviously reduced, the high-efficiency killing activity of the drug on melanoma cells can be completely reserved, and the tumor targeting selectivity is obviously improved. The strategy provides an effective technical path for the accurate treatment of melanoma, has the core potential advantages of strong targeting and high safety, and has wide application prospect. Disclosure of Invention The invention aims to overcome the defects of the existing chemotherapeutic drugs in tumor treatment, especially melanoma, and particularly solves the problem of side effects such as systemic toxicity caused by nonspecific systemic administration of the chemotherapeutic drugs. Therefore, the invention provides a tyrosinase response type medicine design method for melanoma targeted therapy, a medicine designed based on the method, and a preparation method and application thereof, and aims to obtain a precise therapeutic scheme with high selectivity and low toxic and side effects. In a first aspect, the invention provides a tyrosinase-responsive drug design method for melanoma targeted therapy, which is characterized in that the drug is based on a chemotherapeutic drug clinically used for cancer therapy, and a structural unit of 3-hydroxy benzyl alcohol is introduced to realize specific response and activation of tyrosinase to the drug. T