(S, S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)- N-(1-oxo-1-((1-(pyridin-4-yl)ethyl)amino)propan-2-yl)-1 H-indole-2-carboxamide, a New Dishevelled 1 and P-Glycoprotein Dual Inhibitor as a Anticancer Agent

  • J Med Chem. 2026 Jun 25;69(12):14667-14690. doi: 10.1021/acs.jmedchem.6c00706.
Michela Puxeddu  1 ,  Zeyu Cui  2 ,  Claudia Colla  1 ,  Marianna Nalli  1 ,  Simone Manetto  1 ,  Alessia Ciogli  1 ,  Petra Cuřínová  3 ,  Marianna Bufano  3 ,  Angelo Toto  4 ,  Stefano Gianni  4 ,  Arianna Pastore  5 ,  Mariano Stornaiuolo  5 ,  Enke Baldini  6 ,  Salvatore Ulisse  6 ,  Joanna Kopecka  7 ,  Chiara Riganti  7 ,  Chiara Bigogno  8 ,  Giulio Dondio  8 ,  Te Liu  2 ,  Antonio Coluccia  1 ,  Giuseppe La Regina  1 ,  Romano Silvestri  1
Affiliations
  • 1. Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome00185, Italy.
  • 2. Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai200031, China.
  • 3. Department of Organic Chemistry, University of Chemistry and Technology Prague, Technická 5, Prague 616628, Czech Republic.
  • 4. Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Biochemical Sciences "Rossi Fanelli", Institute of Biology and Molecular Pathology of CNR, Sapienza Università di Roma, Piazzale Aldo Moro 5, Rome00185, Italy.
  • 5. Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano, 49, Naples80131, Italy.
  • 6. Department of Surgery, Sapienza University of Rome, Viale Regina Elena 324, Rome00185, Italy.
  • 7. Department of Oncology and Molecular Biotechnology Center ″Guido Tarone″, Via Nizza 44, Turin10126, Italy.
  • 8. Aphad SrL, Via della Resistenza 65, Buccinasco20090, Italy.
PMID: 42283820 DOI: 10.1021/acs.jmedchem.6c00706
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.

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