Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t_1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.

The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting microtubule polymerization, leading to cell cycle arrest and apoptosis in cancer cells and possesses much better pharmaceutical properties. This study investigated the antiproliferative and anti-invasive activities of STX140 in both SKMEL-28 naïve melanoma (SKMEL28-P) cells and resistant melanoma cells (SKMEL-28R). STX140 inhibited cell proliferation in the nanomolar range while having a less pronounced effect on human melanocytes. Additionally, STX140 induced cell cycle arrest in the G2/M phase and sub-G1, reduced migration, and clonogenic potential in monolayer models, and inhibited invasion in a 3D human skin model with melanoma cells. Furthermore, STX140 induced senescence features in melanoma and activated the senescence machinery by upregulating the expression of senescence genes and proteins related to senescence signaling. These findings suggest that STX140 may hold potential as a therapeutic agent for melanoma treatment.

Melanoma lethality is driven by high intratumoral heterogeneity, metastatic competence, and phenotypic plasticity, which foster rapid emergence of resistance to targeted therapies such as BRAF inhibitors (BRAFi, e.g. vemurafenib). Copper(II) complexes have emerged as promising anticancer candidates, yet their activity against BRAFi-resistant melanoma remains poorly defined. Here, we show that the binuclear copper(II) complex [Cu2(apyhist)2dpam](ClO4)4 (herein referred to as [Cu(II)L]) displays low-micromolar cytotoxicity and antiproliferative activity in parental and BRAFi-resistant melanoma models. Binuclear [Cu(II)L] suppresses melanoma migration and invasion and reduces tumor burden and dermal invasion in a reconstructed human skin melanoma model with limited toxicity to normal tissue. Mechanistically, [Cu2(apyhist)2dpam](ClO4)4 triggers a ROS-dependent stress response that is attenuated by N-acetylcysteine, leading to DNA damage, mitochondrial depolarization and caspase-independent cell death. Molecular profiling indicates engagement of cell cycle arrest and stress-adaptation programs, with signatures suggesting ferroptotic-associated, necroptotic and autophagy-related signaling, pointing to a redox-driven, diverse mechanism rather than a single dominant death pathway. Different modulation of key markers (PARP1, H2AX, MLKL, GPX4, LC3B-II, and p62) supports that its multitarget activity can bypass adaptive resistance mechanisms. Collectively, these findings support binuclear [Cu(II)L] as a candidate to target invasive and drug-resistant melanoma phenotypes.

Due to the arising of clinically relevant resistant EGFR‐related phenotype through innovative mechanisms, mainly EGFR _L858R/T790M , the emergence of novel molecules with dual or multi‐target affinity has presented a promising alternative to overcoming these resistance mechanisms. This study aimed to evaluate synthetic acrylamide quinoxaline derivatives against NSCLC cell lines with different overexpressed EGFR mutations and compare their DMPK profile. The biological activity of LASSBio‐1971 and LASSBio‐1974 was assessed through cytotoxicity (MTT and Sulforhodamine B assays), apoptosis induction, EGFR inhibition, cell cycle analysis (flow cytometry), immunofluorescence microscopy, cell membrane permeability (PAMPA assay), and metabolic stability in rat liver microsomes. LASSBio‐1971 exhibited promising EGFR inhibition with favorable in vitro pharmacokinetic (PK) properties, including high gastrointestinal and blood–brain barrier permeability. LASSBio‐1974 demonstrated nonselective mechanism inhibiting EGFR and mitotic machinery leading to apoptosis and cell cycle arrest at different phases. LASSBio‐1971 and LASSBio‐1974 emerge as EGFR inhibitors with equipotent cytotoxic effects on human NSCLC lines and different in PK profile. Further studies should be conducted with LASSBio‐1974 to prove and understand its antimicrotubule action.