The development of new anticancer therapies remains challenging due to tumor heterogeneity and the frequent emergence of multidrug resistance (MDR). Natural products have garnered increasing attention as alternative or complementary therapeutic agents due to their bioactivity and reduced toxicity. Polyphenols, particularly curcumin and its derivatives, have shown promise in modulating signaling pathways, enhancing chemosensitivity, and overcoming drug resistance. The anticancer potential of dimethoxycurcumin, a chemically modified curcumin derivative identified through consensus fingerprint similarity screening, was investigated for its potential to inhibit ABCC3 (MRP3)—a member of the ATP-binding cassette (ABC) transporter family implicated in drug efflux, tumor cell survival, and resistance. In vitro experiments demonstrated that dimethoxycurcumin significantly reduced cancer cell viability and colony formation, indicating a strong inhibitory effect on ABCC3 function. These results suggest that dimethoxycurcumin may sensitize cancer cells to chemotherapy by targeting resistance pathways. The data presented contribute to the growing body of evidence suggesting that bioactive plant-derived compounds, including chemically modified derivatives, may hold therapeutic potential in oncology by modulating multidrug resistance pathways. Targeting ABC transporters with natural compound derivatives could offer a promising strategy for developing more effective and less toxic anticancer therapies.

The development of new anticancer therapies remains challenging due to tumor heterogeneity and the frequent emergence of multidrug resistance (MDR). Natural products have garnered increasing attention as alternative or complementary therapeutic agents due to their bioactivity and reduced toxicity. Polyphenols, particularly curcumin and its derivatives, have shown potential in modulating signaling pathways, enhancing chemosensitivity, and overcoming drug resistance. In this study, we discovered the anticancer potential of Dimethoxycurcumin, a synthetic curcumin analog identified through consensus fingerprint similarity screening. Focusing on the ATP-binding cassette (ABC) transporter family—key mediators of drug efflux—we examined the impact of Dimethoxycurcumin on ABCC3 (MRP3), a transporter implicated in tumor cell survival and resistance. Our in vitro experiments demonstrated that Dimethoxycurcumin significantly reduced cell viability and colony formation, indicating a strong inhibitory effect on ABCC3 function. These results suggest that Dimethoxycurcumin may sensitize cancer cells to chemotherapy by targeting resistance pathways. This study supports the therapeutic value of plant-derived compounds and their derivatives in oncology and contributes to a better understanding of how functional antioxidants may interact with MDR-related transporters. Targeting ABC transporters with natural compound derivatives may offer a promising strategy for developing more effective and less toxic anticancer therapies.

Wee1-like protein kinase (Wee1) is a serine/threonine kinase essential for cell cycle regulation and the DNA damage response (DDR), acting as a tumor suppressor in normal cells. Its overexpression in cancers such as melanoma, hepatocellular carcinoma, and glioblastoma underscores its potential as a therapeutic target. Wee1 inhibition has emerged as a strategy to sensitize tumor cells to genotoxic therapies, though no inhibitors have yet received broad clinical approval. In the first round of screening, we employed ESSENCE-Dock virtual screening to identify potential Wee1 inhibitors from the Eurofins-Villapharma library. Of the 12 compounds experimentally validated, six exhibited IC50 values below 100 µM, with compound 1 demonstrating promising activity (IC50 = 240 nM). Based on this initial hit, we synthesized and tested additional compounds, culminating in compound 20, which showed an almost order of magnitude improvement in potency (IC50 = 33 nM). Structure–activity relationship (SAR) analysis highlighted key activity determinants, including the effects of methyl substitution on the phenylpiperazine and double-chlorine halogenation on the terminal phenyl group. Compound 20 compared favorably to known Wee1 inhibitors such as MK-1775, while maintaining a distinct chemical scaffold. To further validate these findings, molecular dynamics simulations were employed to elucidate the binding interactions and conformational dynamics of the high-affinity compounds. These simulations revealed stabilizing interactions that aligned with the observed SAR trends, solidifying compound 20 as a strong lead for further development. In addition, in vitro ADME profiling demonstrated favorable physicochemical properties and drug-likeness, including high solubility and metabolic stability, supporting its potential as a drug candidate. Kinome-wide profiling at 10 µM revealed modest selectivity, highlighting a key consideration for future optimization.