2. Academic Validation
  3. 3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin

3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin

  • ACS Med Chem Lett. 2017 Apr 26;8(5):521-526. doi: 10.1021/acsmedchemlett.7b00022.
Giuseppe La Regina 1,  Ruoli Bai 2,  Antonio Coluccia 1,  Valeria Famiglini 1,  Sara Passacantilli 1,  Valentina Naccarato 1,  Giorgio Ortar 1,  Carmela Mazzoccoli 3,  Vitalba Ruggieri 3,  Francesca Agriesti 3,  Claudia Piccoli 3 4,  Tiziana Tataranni 3,  Marianna Nalli 1,  Andrea Brancale 5,  Stefania Vultaggio 6,  Ciro Mercurio 6,  Mario Varasi 6,  Concetta Saponaro 7,  Sara Sergio 7,  Michele Maffia 7,  Addolorata Maria Luce Coluccia 7,  Ernest Hamel 2,  Romano Silvestri 1
Affiliations

Affiliations

  • 1 Institut Pasteur Italy-Cenci Bolognetti Foundation, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 2 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 3 Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy.
  • 4 Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.
  • 5 Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, U.K.
  • 6 Experimental Therapeutics Unit, IFOM-the FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, I-20139 Milano, Italy.
  • 7 Clinical Proteomics, Polo Oncologico Giovanni Paolo II, ASL-University of Salento, Piazza Muratore 1, 73100 Lecce, Italy.
PMID: 28523104 DOI: 10.1021/acsmedchemlett.7b00022
Abstract

We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential Anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and Cancer cell growth. ARDAP derivative 10 inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. Compound 10 minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. Compound 10 significantly decreased CML proliferation by inducing G2/M phase arrest and Apoptosis via a mitochondria-dependent pathway. ARDAP 10 augmented the cytotoxic effects of IM in human CML cells. Compound 10 represents a robust lead compound to develop tubulin inhibitors with potential as novel treatments for CML.

Keywords

3-aroyl-1,4-diarylpyrrole; Cancer; chronic myeloid leukemia; synthesis; tubulin.

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