Open AccessDevelopment of Ligand-Drug Conjugates Targeting Melanoma through the Overexpressed Melanocortin 1 Receptor
Author(s) -
Yang Zhou,
Saghar Mowlazadeh Haghighi,
Yi Li,
Lingzhi Wang,
Victor J. Hruby,
Minying Cai
Publication year - 2020
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.0c00072
Subject(s) - camptothecin , melanoma , melanocortin 1 receptor , pharmacology , drug , cytotoxic t cell , drug resistance , chemistry , cancer research , biology , in vitro , biochemistry , phenotype , gene , microbiology and biotechnology
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.