Our services

ADC Review
is made possible by:




Thailanstatin A Disrupts Disease by Inhibiting RNA-polymerase II

Published on 20th June

Scientists at Rice University in Houston, Texas, have synthesized a novel anti-cancer agent, Thailanstatin A, which was originally isolated from a bacterial species collected in Thailand. The novel, extreemely potent, compound fights cancer by inhibiting the machinery in the cell that edits messenger RNA after transcription from DNA but before its translation into proteins.

Rice synthetic chemist K.C. Nicolaou and his group reported their success in the Journal of the American Chemical Society.

thailanstatin-a
Image 1.0: Thailanstatin A. Thailanstatins are splicesosome (RNA-polymerase II) inhibitors are an extremely potent class of anticancer agents used as payloads for novel ADCs.

Nicolaou and his colleagues specialize in the synthesis of potential therapeutic agents that are found in nature but in amounts too small for thorough biological evaluation or clinical use. He is best known for the total synthesis of paclitaxel, a drug commonly used to treat a number of cancers.

Splicesosome
The researchers explained that the spliceosome, a complex of proteins and ribonucleoproteins that regulate DNA splicing, is more active and displays higher mutation rates in cancer cells than in healthy cells, which makes it a valid target for investigation.

“This cellular machinery edits mRNA as it emerges from the transcription of DNA through site-specific removal of introns (noncoding regions of DNA) and splicing the remaining exon (coding) sequences prior to translation,” Nicolaou noted. “Thailanstatin A interferes with this mechanism,” he added.

Burkholderia thailandensis
He said the synthesis of Thailanstatin A, first isolated from burkholderia thailandensis bacteria, opens the way to construct and test variations of the molecule. “These studies will be directed toward optimization of the pharmacological properties of this new natural product as part of a drug discovery and development program targeting new therapies for cancer,” Nicolaou explained.

Antibody-drug conjugate

The program can take two directions, Nicolaou said. One directed toward high-potency compounds that could be used as payloads for antibody-drug conjugates or ADCs and the other toward selective agents that can kill cancer cells with minimal damage to healthy cells.

The first paradigm is currently a frontier approach for the development of targeted and personalized cancer therapies, while the second represents a more traditional approach that could also lead to powerful anti-cancer drugs, Nicolaou said. “Thailanstatin A exhibits just the right potency to be diverted to either approach through a reiterative molecular design, chemical synthesis and biological evaluation process,” he further added.

“We’re excited about this new molecule and its analogs because of their unique biological properties and the prospects of working collaboratively with industrial and academic partners to advance them toward the clinic,” Nicolaou concluded.

The Cancer Prevention and Research Institute of Texas and the Welch Foundation supported the research.


Last Editorial Review: June 20, 2016.

Featured Image: Science laboratory test tubes. Courtesy: © Fotolia. Used with permission. Image 1.0: A schematic shows thailanstatin A. Courtesy: © Rice University. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


Print Friendly, PDF & Email
Share

Leave a Reply


Skip to toolbar