TY - JOUR
T1 - 3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin
AU - La Regina, Giuseppe
AU - Bai, Ruoli
AU - Coluccia, Antonio
AU - Famiglini, Valeria
AU - Passacantilli, Sara
AU - Naccarato, Valentina
AU - Ortar, Giorgio
AU - Mazzoccoli, Carmela
AU - Ruggieri, Vitalba
AU - Agriesti, Francesca
AU - Piccoli, Claudia
AU - Tataranni, Tiziana
AU - Nalli, Marianna
AU - Brancale, Andrea
AU - Vultaggio, Stefania
AU - Mercurio, Ciro
AU - Varasi, Mario
AU - Saponaro, Concetta
AU - Sergio, Sara
AU - Maffia, Michele
AU - Coluccia, Addolorata Maria Luce
AU - Hamel, Ernest
AU - Silvestri, Romano
PY - 2017/5/11
Y1 - 2017/5/11
N2 - 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.
AB - 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.
KW - 3-aroyl-1,4-diarylpyrrole
KW - Cancer
KW - chronic myeloid leukemia
KW - synthesis
KW - tubulin
UR - http://www.scopus.com/inward/record.url?scp=85018898332&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018898332&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.7b00022
DO - 10.1021/acsmedchemlett.7b00022
M3 - Article
AN - SCOPUS:85018898332
VL - 8
SP - 521
EP - 526
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 5
ER -