Treating chronic myeloid leukemia by inhibition of tubulin polymerization

Microtubules are an attractive target for the development of active anti-leukemia agents (1). Despite some evidence, the therapeutic potential of colchicine site binding agents in chronic myeloid leukemia (CML) has not been adequately explored. Recently, starting from previously reported aroylindoles (ARIs, e.g. 1) we have developed 3-aroyl-1-arylpyrroles (ARAPs, e.g. 2) via benzocracking approach (Chart 1) (2). Pursuing our studies, we designed and synthesized 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents (3). ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. (4-(4-Aminophenyl)-1-phenyl-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from 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. The same compound 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. New ARDAP significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via mitochondria-dependent pathway and increased the cytotoxic effects of IM in human CML cells. References. (1) Yeh, Y.-Y.; Liou, J.-P.; Lee, Y.-L. et al. Invest. New Drugs 2017, 35, 427-435. (2) La Regina, G.; Bai, R.; Coluccia, A. et al. J. Med. Chem. 2014, 57, 6531-6552. (3) La Regina, G.; Bai, R.; Coluccia, A. et al. ACS Med. Chem. Lett. 2017, 8, 521-526.