2. Academic Validation
  3. Identification and characterization of SSE15206, a microtubule depolymerizing agent that overcomes multidrug resistance

Identification and characterization of SSE15206, a microtubule depolymerizing agent that overcomes multidrug resistance

  • Sci Rep. 2018 Feb 19;8(1):3305. doi: 10.1038/s41598-018-21642-0.
Safia Manzoor 1,  Aishah Bilal 2,  Sardraz Khan 1,  Rahim Ullah 2,  Sunniya Iftikhar 1,  Abdul-Hamid Emwas 3,  Meshari Alazmi 4,  Xin Gao 4,  Ali Jawaid 2,  Rahman Shah Zaib Saleem 5,  Amir Faisal 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, 54792, Pakistan.
  • 2 Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, 54792, Pakistan.
  • 3 Imaging and Characterization Core Lab, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia.
  • 4 Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia.
  • 5 Department of Chemistry, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, 54792, Pakistan. rahman.saleem@lums.edu.pk.
  • 6 Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, 54792, Pakistan. amir.faisal@lums.edu.pk.
PMID: 29459693 DOI: 10.1038/s41598-018-21642-0
Abstract

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated Cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in Cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different Cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.

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