Development of Ligand-Drug Conjugates Targeting Melanoma through the Overexpressed Melanocortin 1 Receptor

Abstract

Melanoma is a lethal form of skin cancer. Despite recent breakthroughs of BRAF-V600E and PD-1 inhibitors showing remarkable clinical responses, melanoma can eventually survive these targeted therapies and become resistant. To solve the drug resistance issue, we designed and synthesized ligand-drug conjugates that couple cytotoxic drugs, which have a low cancer resistance issue, with the melanocortin 1 receptor (MC1R) agonist melanotan-II (MT-II), which provides specificity to MC1R-overexpressing melanoma. The drug-MT-II conjugates maintain strong binding interactions to MC1R and induce selective drug delivery to A375 melanoma cells through its MT-II moiety in vitro. Furthermore, using camptothecin as the cytotoxic drug, camptothecin-MT-II (compound 1) can effectively inhibit A375 melanoma cell growth with an IC50 of 16 nM. By providing selectivity to melanoma cells through its MT-II moiety, this approach of drug-MT-II conjugates enables us to have many more options for cytotoxic drug selection, which can be the key to solving the cancer resistant problem for melanoma.

Late-Stage Functionalization with Cysteine Staples Generates Potent and Selective Melanocortin Receptor-1 Agonists

“…The stapling strategies developed in the bicyclic MCR peptides also provide opportunities for further transformations to build peptide conjugates and explore other drug design avenues. For example, MC1R has attracted attention as a potential molecular target for development of therapeutics and diagnostics in malignant melanoma because this receptor is overexpressed in a large proportion of these cell types. , Peptide conjugates, where an MCR-targeting epitope is linked to a cytotoxic molecule or diagnostic agent, are an attractive option, − but the diversity of conjugation technologies employed in the context of MCR is almost exclusively reliant on amide-forming chemistry, typically requiring protected peptide substrates and often employing synthetic approaches that are difficult to rapidly diversify or to explore structure activity relationships. ,, This motivated us to further expand the bicyclic stapled peptide analogues by using functionalization chemistry on the unprotected peptide analogues to further build and evaluate how various linkers and payloads influence the pharmacology of the conjugates at MC1R.…”

Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects

“…Bremelanotide (PT-141), an acid derivative of melanotan II, acts as an agonist of the MC1R and MC4R and has been demonstrated to increase erectile function and sexual desire (Figure 6) [112,113]. In 2020, Zhou et al reported an attractive study in which melanotan II was utilized as a probe for selective drug delivery [114,115]. The authors synthesized and designed ligand-drug conjugates with the melanocortin 1 receptor (MC1R) agonist melanotan-II (MT-II) to couple a cytotoxic drug, camptothecin with low cancer resistance (Figure 7).…”

“…This approach of drug-MT-II conjugates offers more options in cytotoxic drug selection and is noteworthy for potentially overcoming the cancer-resistant problem of melanoma. In 2020, Zhou et al reported an attractive study in which melanotan II was utilized as a probe for selective drug delivery [114,115]. The authors synthesized and designed ligand-drug conjugates with the melanocortin 1 receptor (MC1R) agonist melanotan-II (MT-II) to couple a cytotoxic drug, camptothecin with low cancer resistance (Figure 7).…”

“…In 2020, Zhou et al reported an attractive study in which melanotan II was utilized as a probe for selective drug delivery [114,115]. The authors synthesized and designed ligand-drug conjugates with the melanocortin 1 receptor (MC1R) agonist melanotan-II (MT-II) to couple a cytotoxic drug, camptothecin with low cancer resistance (Figure 7).…”

Targeting the Melanocortin 1 Receptor in Melanoma: Biological Activity of α-MSH–Peptide Conjugates

“…In cyclic versions, the Lys 11 is often replaced by Arg, suggesting that the Lys side chain is not necessary for receptorbinding affinity [17,18]. The α-MSH radiolabeled analogs have been predominantly used as diagnostic tools in the field of melanoma research, but only a few studies have investigated their chemotherapeutic applications [12,13,15,17,[19][20][21][22][23][24][25][26]. Melphalan (phenylalanine mustard: PAM) was attached either to the side chain of Lys in position 11 (because it is not part of the main receptor recognition site of α-MSH) or to the N-terminus; furthermore, the Arg 8 was replaced by PAM.…”