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
  • 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.