Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.
Susan Matthew,Qi-Yin Chen,Ranjala Ratnayake,Charles S. Fermaintt,Daniel Lucena-Agell,Francesca Bonato,Andrea E. Prota,Seok Ting Lim,Xiaomeng Wang,J. Fernando Díaz,April L. Risinger,Valerie J. Paul,María A. Oliva,Hendrik Luesch,Hendrik Luesch +14 more
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TLDR
In this paper, a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), was discovered at the tubulin intradimer interface.Abstract:
Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin-GB1 complex.read more
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Marine natural products.
TL;DR: A review of the literature published in 2020 for marine natural products (MNPs), with 757 citations (747 for the period January to December 2020) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms as discussed by the authors .
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Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles
TL;DR: A review of microtubule-targeting agents (MTAs) can be found in this paper, where the authors review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.
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Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation
TL;DR: The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance as discussed by the authors .
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Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation
Wei Liu,Hairui Jia,Minghao Guan,Cui Minxuan,Lan Zhuxuan,He Youyou,Zhongjie Guo,Ru Jiang,Guoqiang Dong,Shengzheng Wang +9 more
TL;DR: The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance as mentioned in this paper.
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Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action
Tobias Mühlethaler,Lampros Milanos,José Antonio Ortega,Thorsten B. Blum,D. Gioia,Bibhas Roy,Andrea Prota,Andrea Cavalli,Michel O. Steinmetz +8 more
TL;DR: The generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action, demonstrates the usefulness of tubulin‐binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns.
References
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