Development of tubulin polymerization inhibitors as anticancer agents

ABSTRACT

Introduction

Microtubules are intracellular, filamentous, polymeric structures that extend throughout the cytoplasm, composed of α-tubulin and β-tubulin subunits. They regulate many cellular functions including cell polarity, cell shape, mitosis, intracellular transport, cell signaling, gene expression, cell integrity, and are associated with tumorigenesis. Inhibition of tubulin polymerization within tumor cells represents a crucial focus in the pursuit of developing anticancer treatments.

Areas Covered

This review focuses on the natural product and their synthetic congeners as tubulin inhibitors along with their site of interaction on tubulin. This review also covers the developed novel tubulin inhibitors and important patents focusing on the development of tubulin inhibition for cancer treatment reported from 2018 to 2023. The scientific and patent literature has been searched on PubMed, Espacenet, ScienceDirect, and Patent Guru from 2018–2023.

Expert opinion

Tubulin is one of the promising targets explored extensively for drug discovery. Compounds binding in the colchicine site could be given importance because they can elude resistance mediated by the P-glycoprotein efflux pump and no colchicine site binding inhibitor is approved by FDA so far. The research on the development of antibody drug conjugates (ADCs) for tubluin polymerization inhibition could be significant strategy for cancer treatment.

KEYWORDS:

• Microtubules
• tubulin polymerization inhibitors
• drug discovery
• cancer treatment
• patents

Article highlights

• Microtubules are cellular components that are required for a variety of essential processes such as cell motility, mitosis, and intracellular transport.

• Microtubules are associated with tumorigenesis and represent interesting therapeutic target for the development of clinically useful anticancer drugs.

• Tubulin inhibitors are found to interact at multiple sites on tubulin and around seven classes of these compounds have been visualized in crystal structures.

• Colchicine binding site is the site of interest for current research.

• Antibody drug conjugates containing tubulin inhibitor is one of important strategy to develop promising tubulin polymerization inhibitors.

Acknowledgments

M. N. Peerzada acknowledges the Indian Council of Medical Research (ICMR) New Delhi, Department of Health Research, Government of India for funding (No. 3/1/3PDF(24)/2021-HRD-6) in the form of ICMR-postdoctoral fellowship. We are thankful to Dr. Krishna Kishore Inampudi and Dr. Sudhir Chandra Sarangi from All India Institute of Medical Sciences, New Delhi for their support in this research work.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

M. N. Peerzada collected the data and wrote the manuscript, M.S. Dar wrote and edited the manuscript, and S. Verma wrote and edited the manuscript.

Additional information

Funding

This paper was funded by the Indian Council of Medical Research (No. 3/1/3PDF(24)/2021-HRD-6).