Dishevelled (DVL) proteins are key mediators of the Wnt/β-catenin signaling pathway, involved in signal transduction from membrane receptors to intracellular effectors. DVL up-regulation has often been correlated with tumor progression and metastasis. DVL1 was found overexpressed in multidrug-resistant colorectal cancer (CRC) cells. Here, we describe the synthesis of new indole-2-carboxamides 2-18 as DVL1 inhibitors. Compound (S,S)-15 showed potent DVL1 inhibition with IC50 of 0.97 ± 0.21 μM and specific binding to the DVL1 PDZ domain. (S,S)-15 strongly reduced β-catenin expression in HCT116 CRC cells and significantly decreased tumor volume and weight in a xenograft model. Additionally, (S,S)-15 inhibited P-glycoprotein (P-gp), restoring sensitivity to doxorubicin (DOX) in HT29/DX CRC chemoresistant cells. (S,S)-15 demonstrated high metabolic stability in human liver microsomes, and an acceptable pharmacokinetic profile following IV administration in mice. Our findings indicate that compound (S,S)-15 represents a promising dual-targeting antitumor candidate for CRC treatment.
(S,S)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((1-(pyridin-4-yl)ethyl)amino)propan-2-yl)-1H-indole-2-carboxamide, a new Dishevelled 1 and P-glycoprotein dual inhibitor as anticancer agent / Puxeddu, M., Cui, Z., Colla, C., Nalli, M., Manetto, S., Ciogli, A., Cuřínová, P., Bufano, M., Toto, A., Gianni, S., Pastore, A., Stornaiuolo, M., Baldini, E., Ulisse, S., Kopecka, J., Riganti, C., Bigogno, C., Dondio, G., Liu, T.e., Coluccia, A., et al.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 69:12(2026), pp. 14667-14690. [10.1021/acs.jmedchem.6c00706]
(S,S)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((1-(pyridin-4-yl)ethyl)amino)propan-2-yl)-1H-indole-2-carboxamide, a new Dishevelled 1 and P-glycoprotein dual inhibitor as anticancer agent
Puxeddu, Michela
;Colla, Claudia;Nalli, Marianna;Manetto, Simone;Ciogli, Alessia;Bufano, Marianna;Toto, Angelo;Gianni, Stefano;Pastore, Arianna;Baldini, Enke;Ulisse, Salvatore;Liu, Te
;Coluccia, Antonio;Regina, Giuseppe La;Silvestri, Romano
2026
Abstract
Dishevelled (DVL) proteins are key mediators of the Wnt/β-catenin signaling pathway, involved in signal transduction from membrane receptors to intracellular effectors. DVL up-regulation has often been correlated with tumor progression and metastasis. DVL1 was found overexpressed in multidrug-resistant colorectal cancer (CRC) cells. Here, we describe the synthesis of new indole-2-carboxamides 2-18 as DVL1 inhibitors. Compound (S,S)-15 showed potent DVL1 inhibition with IC50 of 0.97 ± 0.21 μM and specific binding to the DVL1 PDZ domain. (S,S)-15 strongly reduced β-catenin expression in HCT116 CRC cells and significantly decreased tumor volume and weight in a xenograft model. Additionally, (S,S)-15 inhibited P-glycoprotein (P-gp), restoring sensitivity to doxorubicin (DOX) in HT29/DX CRC chemoresistant cells. (S,S)-15 demonstrated high metabolic stability in human liver microsomes, and an acceptable pharmacokinetic profile following IV administration in mice. Our findings indicate that compound (S,S)-15 represents a promising dual-targeting antitumor candidate for CRC treatment.| File | Dimensione | Formato | |
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