Utilize conjugated melanotropins for the earlier diagnosis and treatment of melanoma

Cai, Minying; Liu, Zhonglin; Qu, Hongchang; Fan, Helen; Zheng, Zhiping; Hruby, Victor J.

doi:10.1016/j.ejphar.2011.01.032

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…This kinetic advantage can be very useful in detecting cancer vs. non-cancer tissue. This kinetic advantage also should be applicable for in vivo imaging for detection of cancer following cancer treatments [72–75]. …”

Section: Multivalency and The Melanocortin Systemmentioning

confidence: 99%

The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases

Cai¹,

Hruby

2016

CPPS

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The melanocortin receptor system consists of five closely related G-protein coupled receptors (MC1R, MC2R, MC3R, MC4R and MC5R). These receptors are involved in many of the key biological functions for multicellular animals, including human beings. The natural agonist ligands for these receptors are derived by processing of a primordial animal gene product, proopiomelanocortin (POMC). The ligand for the MC2R is ACTH (Adrenal Corticotropic Hormone), a larger processed peptide from POMC. The natural ligands for the other 4 melanocortin receptors are smaller peptides including α-melanocyte stimulating hormone (α-MSH) and related peptides from POMC (β-MSH and γ-MSH). They all contain the sequence His-Phe-Arg-Trp that is conserved throughout evolution. Thus, there has been considerable difficulty in developing highly selective ligands for the MC1R, MC3R, MC4R and MC5R. In this brief review, we discuss the various approaches that have been taken to design agonist and antagonist analogues and derivatives of the POMC peptides that are selective for the MC1R, MC3R, MC4R and MC5R receptors, via peptide, nonpeptide and peptidomimetic derivatives and analogues and their differential interactions with receptors that may help account for these selectivities.

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Section: Multivalency and The Melanocortin Systemmentioning

confidence: 99%

The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases

Cai¹,

Hruby

2016

CPPS

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“…The MC1R is expressed on various cells of the immune system such as cytotoxic T cells and dendritic cells, where it exerts anti-inflammatory and immunomodulatory effects [3,4]. MC1R is overexpressed on most of the melanoma cells, which makes it the identification tag for melanoma imaging and therapy [5,6]. The MC2R is expressed in the adrenal cortex, where it regulates the production of glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

Novel approaches to the design of bioavailable melanotropins

Zhou

Cai

2017

Expert Opinion on Drug Discovery

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Introduction The melanocortin system is a primordial and critical system for survival, involved in a wide variety of physiological functions. It includes melanocortin receptors (MCRs) and melanotropin ligands (MCLs). MCRs are important drug targets that can regulate several key physiological processes. Extensive efforts have been made to develop peptide and peptidomimetics targeting melanocortin receptors including MC1R, MC3R, MC4R and MC5R. Most research is focused on developing potent and selective melanotropins. However, developing bioavailable melanotropins remains challenging. Areas covered Herein, the authors summarize promising strategies for developing bioavailable MCLs by using cyclized N-methylated melanotropins, and using cyclotide and tetrapeptide as templates. They discuss their unique advantages in oral availability and targeting MCRs in the central nervous system or in peripheral tissues. Finally, they discuss the observed differences in thepharmacology of MCRs between in vitro and in vivo tests. Expert opinion N-methylated cyclized melanotropins have great potential to become bioavailable drugs targeting MCRs in the brain, while MCR-grafted cyclotides tend to target MCRs in peripheral tissue. A better understanding of the biased signaling process is a new challenge and opportunity for the future discovery of bioavailable MCLs.

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“…Upon sun exposure, the endogenous agonist α-melanocyte-stimulating hormone (α-MSH) is produced, which activates MC1R on melanocytes to induce melanin production and skin pigmentation . MC1R is found to be highly expressed in 80% of malignant melanomas, and thus has been demonstrated as a selective target for melanoma imaging. − Even with nonselective peptide ligands that can also bind to other melanocortin receptor subtypes, the in vivo imaging studies demonstrated high melanoma uptake and low normal organ uptake except for the kidney. , Ever since its development, the cyclized peptide melanotan-II (Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH 2 , MT-II) has been widely used as melanocortin receptor agonists due to its strong potency and serum stability . MT-II also serves as a template for further modifications and conjugations to improve its selectivity, oral bioavailability, and to expand its applications (such as melanoma imaging and therapy , ).…”

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confidence: 99%

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

Zhou

Haghighi

et al. 2020

ACS Pharmacol. Transl. Sci.

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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.

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Utilize conjugated melanotropins for the earlier diagnosis and treatment of melanoma

Cited by 3 publications

References 31 publications

The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases

The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases

Novel approaches to the design of bioavailable melanotropins

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

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