Conjugation of MCR1 ligand with cytotoxic drugs for treating skin cancer

Patent metadata

Field	Value
Publication number	US-12440570-B2
Application number	US-202217579237-A
Country	US
Kind code	B2
Filing date	Jan 19, 2022
Priority date	Jul 19, 2019
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

Ligand-drug conjugates for targeted melanoma therapies are disclosed herein. A ligand is conjugated to a cytotoxic cancer drug through a cleavage linker. The ligand can bind to an overexpressed receptor on a cancer cell, resulting in selectivity. This allows the drug to enter a cancer cell selectively and release the drug within that specific cancer cell. Such therapies provide selectivity to melanoma through a ligand that targets the MC1R receptor, which is highly expressed in 80% of malignant melanomas. The ligand-drug conjugates can be used to deliver a wide range of cytotoxic cancer drugs selective to melanoma cells which may solve the drug resistance problem of melanoma in current therapies.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a ligand-drug conjugate comprising a peptide ligand bound to a drug moiety, wherein the ligand-drug conjugate is according to the formula: L-A-B-D, wherein L is the peptide ligand, A is a spacer derived from aminohexanoic acid, B is a cleavable linker, and D is the drug moiety, wherein the peptide ligand is according to the formula:
Ac-Nle-c[Asp-His-Taa-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 89), or is a derivative that has at least 50% homology to SEQ ID NO: 89, wherein Taa is DPhe or DNal(2′).

2. The composition of claim 1 , wherein the derivative has at least 60% homology, at least 70% homology, at least 80% homology, or at least 90% homology to SEQ ID NO: 89.

3. The composition of claim 1 , wherein the peptide ligand has at least one backbone residue that is N-methylated.

4. The composition of claim 1 , wherein the peptide ligand is one of the following:
Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 4);
Ac-Nle-c[Asp-His-DNal(2)-Arg-Trp-Lys]-NH 2 (SEQ ID NO: 5); or a derivative that has at least 50% homology to SEQ ID NO: 4 or SEQ ID NO: 5.

5. The composition of claim 4 , wherein the derivative has at least 60% homology, at least 70% homology, at least 80% homology, or at least 90% homology to SEQ ID NO: 4, or SEQ ID NO: 5.

6. The composition of claim 4 , wherein the peptide ligand has at least one backbone residue that is N-methylated.

7. The composition of claim 1 , wherein the peptide ligand is one of the following:

 (SEQ ID NO: 7)

Ac-Nle-c[Asp-His-DPhe-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 8)

Ac-Nle-c[Asp-His-DPhe-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 9)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 10)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 11)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 12)

Ac-Nle-c[Asp-His-DPhe-Arg-(NMe)Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 13)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 14)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 15)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-Trp-(NMe)Lys]-NH 2

 (SEQ ID NO: 16)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 17)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 18)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-(NMe)Trp-Lys]-NH 2

 (SEQ ID NO: 19)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 20)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 21)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-Trp-Lys]-NH 2

 (SEQ ID NO: 22)

Ac-Nle-c[Asp-His-DPhe-(NMe)Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 23)

Ac-Nle-c[Asp-His-(NMe)DPhe-Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 24)

Ac-Nle-c[Asp-(NMe)His-DPhe-Arg-(NMe)Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 25)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 26)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 27)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-Trp-(NMe)Lys]-

NH 2

 (SEQ ID NO: 28)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 29)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 30)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-(NMe)Trp-Lys]-

NH 2

 (SEQ ID NO: 31)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-(NMe)Arg-Trp-Lys]-

NH 2

 (SEQ ID NO: 32)

Ac-Nle-c[Asp-His-(NMe)DPhe-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 33)

Ac-Nle-c[Asp-(NMe)His-DPhe-(NMe)Arg-(NMe)Trp-

(NMe)Lys]-NH 2

 (SEQ ID NO: 34)

Ac-Nle-c[Asp-(NMe)His-(NMe)DPhe-Arg-(NMe)Trp-

(NMe)Lys]-NH 2

Assignees

• Univ Arizona

Inventors

• Cai Minying
• Hruby Victor J
• Zhou Yang

Classifications

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C07K14/70571

  for neuromediators, e.g. serotonin receptor, dopamine receptor · CPC title