A Pyrroloquinoline-Based Colchicine-Binding Site Inhibitor Drives Mitotic Arrest and Caspase-Dependent Apoptosis
- 1Middle Tennessee State University , , , ,
- 2University of Tennessee Health Science Center , , , ,
Abstract
Targeting the colchicine-binding site on tubulin represents a promising strategy for developing anticancer agents capable of overcoming drug resistance and alleviating limitations of current microtubule-targeting therapies. Building on the pharmacological potential of quinoline scaffolds, we designed pyrroloquinoline-based compounds aimed at targeting the colchicine-binding site on tubulin. A hypothesis-driven design strategy, guided by structure- and ligand-based molecular modeling, was employed to prioritize the designed molecules for strong predicted binding and pharmacophoric complementarity within the colchicine-binding site. A concise, efficient synthetic strategy was employed to access the target molecules, which were subsequently evaluated for antiproliferative activity across various cancer cell lines. The hit compounds reported in this paper, 4a and 5b, exhibited potent cytotoxicity, competitively inhibited the formation of the EBI−β-tubulin adduct, and induced pronounced disruption of the intracellular microtubule network. Compound 4a, in particular, consistently displayed significant biological activity, as mechanistic studies revealed that it triggers sustained G2/M phase arrest, suppresses proliferative signaling, and activates DNA damage–associated stress responses, followed by caspase-3 activation and PARP cleavage, indicative of caspase-dependent apoptosis. These results reinforce the utility of the quinoline scaffold for the development of colchicine-site microtubule inhibitors and highlight their potential in advancing new chemotherapeutic candidates.
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BibTeX
@article{garain2026pyrroloquinolinebased,
title = {{A Pyrroloquinoline-Based Colchicine-Binding Site Inhibitor Drives Mitotic Arrest and Caspase-Dependent Apoptosis}},
author = {Tanya Garain and Shelby Waddell and Prateek Rai and Cinthia N. Reed and Brittney D. Williams and Joy M. Harrison and Christopher J. Clark and Faben Zeleke and Samara Barnes and Dejian Ma and Jason R. Jessen and Kevin L. Bicker and April M. Weissmiller and Wei Li and Souvik Banerjee},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c07991},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c07991/5460941/A-Pyrroloquinoline-Based-Colchicine-Binding-Site},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A Pyrroloquinoline-Based Colchicine-Binding Site Inhibitor Drives Mitotic Arrest and Caspase-Dependent Apoptosis
AU - Tanya Garain
AU - Shelby Waddell
AU - Prateek Rai
AU - Cinthia N. Reed
AU - Brittney D. Williams
AU - Joy M. Harrison
AU - Christopher J. Clark
AU - Faben Zeleke
AU - Samara Barnes
AU - Dejian Ma
AU - Jason R. Jessen
AU - Kevin L. Bicker
AU - April M. Weissmiller
AU - Wei Li
AU - Souvik Banerjee
PY - 2026
DA - 2026/10/29
JO - ACS Omega
DO - 10.1021/acsomega.6c07991
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c07991/5460941/A-Pyrroloquinoline-Based-Colchicine-Binding-Site
AB - Targeting the colchicine-binding site on tubulin represents a promising strategy for developing anticancer agents capable of overcoming drug resistance and alleviating limitations of current microtubule-targeting therapies. Building on the pharmacological potential of quinoline scaffolds, we designed pyrroloquinoline-based compounds aimed at targeting the colchicine-binding site on tubulin. A hypothesis-driven design strategy, guided by structure- and ligand-based molecular modeling, was employed to prioritize the designed molecules for strong predicted binding and pharmacophoric complementarity within the colchicine-binding site. A concise, efficient synthetic strategy was employed to access the target molecules, which were subsequently evaluated for antiproliferative activity across various cancer cell lines. The hit compounds reported in this paper, 4a and 5b, exhibited potent cytotoxicity, competitively inhibited the formation of the EBI−β-tubulin adduct, and induced pronounced disruption of the intracellular microtubule network. Compound 4a, in particular, consistently displayed significant biological activity, as mechanistic studies revealed that it triggers sustained G2/M phase arrest, suppresses proliferative signaling, and activates DNA damage–associated stress responses, followed by caspase-3 activation and PARP cleavage, indicative of caspase-dependent apoptosis. These results reinforce the utility of the quinoline scaffold for the development of colchicine-site microtubule inhibitors and highlight their potential in advancing new chemotherapeutic candidates.
SN - 2470-1343
ER -