Dear Colleagues,

The microtubule is a prime target for anticancer drugs and, more recently, for drugs to treat neurodegeneration. Drugs that stabilize or destabilize microtubules reduce their ability to dynamically shorten or grow, respectively, and have been a mainstay in the effective treatment of cancer for decades. The efficacy of newer cancer therapeutics that target specific receptor-signaling pathways in the cell are often compromised through up-regulation of compensatory pathways. However, there is no back-up system when microtubule function is compromised, which has led to the continued development of new agents that disrupt these critical structures both as single agents and in combination with targeted therapeutics. Clinical trials are also in progress to explore the ability of these drugs to inhibit the progression or reverse defects in neuronal fast axonal transport in neurodegenerative diseases, such as Alzheimer's disease. This Special Issue will concentrate on the use of microtubule-targeting agents (MTAs), including both microtubule stabilizers (MSAs) and destabilizers (MDAs), to treat disease.

The MDA colchicine, from the autumn crocus, was used in its plant form to treat rheumatism and swelling as far back as 1500 BC. At the turn of the 19th century, the antimitotic activities of colchicine were described, and it was critical in the identification of tubulin as the main microtubule component in the 1960s. While colchicine itself is too toxic for effective cancer treatment, there are a large number of compounds that bind within the colchicine site on tubulin that are currently undergoing preclinical and clinical evaluations. The Vinca alkaloids were first discovered in the 1950s and this class of MDAs continues to be a mainstay in the treatment of many cancers. The most recent MDA to enter the clinical treatment of cancer is Halaven^® (eribulin), which binds near the Vinca site but has distinct biological consequences and patient efficacy profiles. Susan Horwitz was the first to describe an MSA (paclitaxel, Taxol^®) in 1979. Following this discovery, research on MSAs has expanded exponentially with many new stabilizing compounds being discovered and clinically developed. Although several MSAs are  currently used in the clinic, including Taxol^® (paclitaxel), Taxotere^® (docetaxel), Ixempra^® (ixabepilone), Abraxane ^® (nanoparticle albumin-bound paclitaxel), and Jetvana^® (cabazitaxel), each of these drugs bind within the same taxane site on the microtubule. There are numerous areas of active research on MTAs that are of interest, including critical insights into the mechanisms of action of these effective agents that extend far beyond their antimitotic effects. This Special Issue is seeking research papers and reviews to highlight the current state of knowledge in this rapidly expanding field. Areas of particular interest include:

• New natural products, their congeners and synthetic analogs, as well as novel small molecule stabilizers and destabilizers with good potency and potential for translation to the clinic.
• Design and synthesis of MTA analogs. For example, chemical scaffolds are being reconstructed based on in silico modeling and structure-activity relationships to simplify chemical structures and produce easier-to-synthesize MTAs that still retain potent anti-microtubule activity. Modification may also improve MTA solubility and perhaps enhance access to the brain. For example, the MSA epothilone D more readily crosses the blood–brain barrier than paclitaxel and may prove more effective than paclitaxel for treatment of brain tumors/metastasis or neuronal degenerative diseases.
• The molecular mechanisms of stabilization and destabilization and their relation to binding sites on tubulin. Allosteric changes in tubulin following the binding of an MTA and the effect of MTAs on the dynamicity of mitotic spindles and interphase microtubules are also areas of interest.
• The structure of the tubulin-MTA complex. Recent research has expanded on the initial structural studies from the 1990s using electron crystallography of zinc-induced sheets of antiparallel protofilaments to new approaches involving X-ray crystallography of MTAs bound to tubulin heterodimers and cryo-electron microscopy of MTA-bound microtubules.
• The interactions between microtubules and endogenous microtubule-associated proteins (MAPs) that act as stabilizing or destabilizing agents, such as tau protein. The interactions of plus and minus end targeting agents on microtubule function is a developing area of investigation.
• The interplay between MTAs and motor proteins. This is a major topic that has important connotations for microtubule function in the interphase cell.
• The effects of microtubule disruption by MTAs on cellular signaling pathways that inform on their anticancer efficacy and potential biomarkers of response to specific drugs of this class.

Reviews or research papers on any of the above topics would be suitable for inclusion in the Special Issue, and we welcome submissions on or around these topics.

Prof. John H. Miller
Prof. Susan Mooberry
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

• microtubule
• microtubule-stabilizing agents
• x-ray crystallography
• Cryo-electron microscopy
• anticancer drug
• Alzheimer's Disease
• microtubule-associated proteins