Nintedanib‐α_Vβ₃ Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma

Abstract

Dedicated to Professor Cesare Gennari on the occasion of his 70th birthday.Melanoma is the deadliest form of skin cancer, and more than 150,000 cases are diagnosed every year in Europe. New strategies in treatment approved over the past decade, such as immunotherapy and targeted therapy, have prolonged life expectation even in stage IV melanoma patients. However, due to the increasing incidence of this cancer, the development of new therapeutic strategies remains urgent. Recent studies revealed the combination of nintedanib, a tyrosine kinase inhibitor approved as an antifibrotic drug, and immuno-and/or targeted therapy drugs to be promising. Here we present three new dual covalent conjugates, in which a nintedanib unit is permanently linked to a cyclopeptidomimetic ligand for the α V β 3 integrin, a transmembrane receptor involved in cell survival, proliferation and migration, which is overexpressed by tumour cells, and therefore recognized as marker for tumour targeting. In vitro assays on human melanoma tumour cells confirmed the high binding affinity of these conjugates for α V β 3 integrin-positive melanoma cells, as well as their integrinmediated cell internalization. Two of these conjugates were efficient in inhibiting the mitogen activated protein kinase (MAPK) signalling pathway, common to both integrin-and growth factor-biological targets. Such targeted conjugates could therefore be of special interest in melanoma treatment alone or in combination with other anticancer drugs.

Small molecule– and peptide–drug conjugates addressing integrins: A story of targeted cancer treatment

“…Tetraphenylethene (TPE) or 1-methyl-1,2,3,4,5-pentaphenylsilole represents such molecules and consists of several conjugated phenyl residues. [130,302] Han et al [130] designed and synthesised a TPE-containing conjugate where the AIE probe is connected via a cathepsin B cleavable Gly-Phe-Leu-Gly peptide to a solubility-enhancing pentaglutamate followed by the Gly-Lys-Gly tripeptide and the integrin addressing DGR (Asp-Gly-Arg) peptide (Table 4.4, entry 10; Nintedanib K562, SSM2c, WM266-4 cells Tyrosine kinase inhibition and blocking angiogenesis [307] Abbreviation: yl =propargylglycine.…”

“…The resulting images revealed that the conjugate reduced angiogenesis more efficiently compared to the unloaded homing device as well as to the combined treatment with sunitinib and the homing device. [200] Bugatti et al [307] used the same linker and RAFT systems as previously described for Sartori et al [200] in combination with the tyrosine kinase inhibitor nintedanib as payload. In addition to two monomeric conjugates a dimeric conjugate, with two c (AmproRGD) units was synthesised and revealed no improved cellular uptake or cell adhesion inhibition abilities in comparison to the monomeric conjugates.…”

“…In anti-proliferation assays an effect was determined in a micromolar range which seems to be induced by the ligand due to a similar performance of the c(AmproRGD) ligand alone. [307] Majewski et al [304] designed a dual-targeting conjugate comprising a protease-activated receptor (PAR) inhibitor, instead of a tyrosine kinase inhibitor and a cyclic RGD peptide or a small molecule RGD peptidomimetic (Table 4.5, entry 4; Figure 4.16). The peptidomimetic was synthesised in accordance with tyrosine-based RGD mimetics developed in the Kessler group.…”

Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGFβ-Induced EMT in Human Non-Small Cell Lung Cancer

“…Cytofluorimetric analysis of K562 erythroleukemia cells revealed that they do not express either αvβ6 or αvβ3 integrin receptors (PMID: 35664627); therefore, these cells were used as a negative control (Figure S3A). In addition, we evaluated αvβ6 integrin expression on human melanoma cells (SSM2c, Figure S4A) and murine fibroblasts (L929, Figure S5A), whereas expression of the αvβ3 integrin receptor in these cells had been previously evaluated [35,39]. murine fibroblasts (L929, Figure S5A), whereas expression of the αvβ3 integrin receptor in these cells had been previously evaluated [35,39].…”

“…In addition, we evaluated αvβ6 integrin expression on human melanoma cells (SSM2c, Figure S4A) and murine fibroblasts (L929, Figure S5A), whereas expression of the αvβ3 integrin receptor in these cells had been previously evaluated [35,39]. murine fibroblasts (L929, Figure S5A), whereas expression of the αvβ3 integrin receptor in these cells had been previously evaluated [35,39].…”