TY - JOUR
T1 - Development of Ligand-Drug Conjugates Targeting Melanoma through the Overexpressed Melanocortin 1 Receptor
AU - Zhou, Yang
AU - Mowlazadeh Haghighi, Saghar
AU - Liu, Zekun
AU - Wang, Lingzhi
AU - Hruby, Victor J.
AU - Cai, Minying
N1 - Funding Information: This work was supported in part by grants from the U.S. Public Health Service, National Institutes of Health, Grants DK017420 and GM 108040, and Proof of Concept grant from the University of Arizona Tech Launch Transfer. We would like to thank the Marley Light Microscopy Facility at the University of Arizona for their assistance in the confocal microscopy studies. Publisher Copyright: Copyright © 2020 American Chemical Society.
PY - 2020/10/9
Y1 - 2020/10/9
N2 - 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.
AB - 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.
KW - GPCR internalization
KW - MC1R
KW - ligand-drug conjugate
KW - melanoma
KW - targeted cancer therapy
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U2 - https://doi.org/10.1021/acsptsci.0c00072
DO - https://doi.org/10.1021/acsptsci.0c00072
M3 - Article
SN - 2575-9108
VL - 3
SP - 921
EP - 930
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 5
ER -