@article{5aafc5973b9a4a7e972639b57e853e48,
title = "Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site",
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.",
keywords = "Cyanobacteria, Marine natural product, Microtubules, Total synthesis, Tubulin",
author = "Susan Matthew and Chen, {Qi Yin} and Ranjala Ratnayake and Fermaintt, {Charles S.} and Daniel Lucena-Agell and Francesca Bonato and Prota, {Andrea E.} and Lim, {Seok Ting} and Xiaomeng Wang and D{\'i}az, {J. Fernando} and Risinger, {April L.} and Paul, {Valerie J.} and Oliva, {Maria {\'A}ngela} and Hendrik Luesch",
note = "Funding Information: supported by grants Ministerio de Ciencia e Innovaci{\'o}n PID2019-10454RB-I00/ AEI/10.13039/501100011033, Fondo de Investigaciones Sanitarias and COV20/ 01007E Proyecto Intramural Especial 201920E111 from Consejo Superior de Investigaciones Cient{\'i}ficas (to J.F.D.) and European Union H2020-MSCA-ITN-2019 860070 TUBINTRAIN grant (to J.F.D. and A.E.P.). We thank staff of the Smithsonian Marine Station for assistance with sample collection and extraction. We thank Wesley Yoshida (University of Hawaii at Manoa) for assistance with the 15N NMR experiments and Long H. Dang (UF Department of Medicine) for providing the HCT116 knockout cells. We thank Susan L. Mooberry (University of Texas Health Science Center at San Antonio) for support with the pharmacological studies; she acknowledges Greehey Endowment support. We thank John A. Beutler of the Molecular Targets Program at the National Cancer Institute for assistance with COMPARE analysis. We thank Ganader{\'i}a Fer-nando D{\'i}az for calf brains supply, and thank staff of beamline XALOC (ALBA, Cerdanyola del Vall{\`e}s, Spain) for their support. We thank Cora Petersen for her assistance with the cell proliferation studies. Funding Information: ACKNOWLEDGMENTS. This research was supported by the NIH, National Cancer Institute Grants R01CA172310 (to H.L.) and R50CA211487 (to R.R.) and National Institute of General Medical Sciences Grant P41GM086210 (to H.L. and V.J.P.), Commercialization Fund Award from University of Florida (UF) Innovate (UF Office of Technology Licensing), and Debbie and Sylvia DeSantis Chair professorship (H.L.). The biochemical and the crystal structure work was Funding Information: This research was supported by the NIH, National Cancer Institute Grants R01CA172310 (to H.L.) and R50CA211487 (to R.R.) and National Institute of General Medical Sciences Grant P41GM086210 (to H.L. and V.J.P.), Commercialization Fund Award from University of Florida (UF) Innovate (UF Office of Technology Licensing), and Debbie and Sylvia DeSantis Chair professorship (H.L.). The biochemical and the crystal structure work was supported by grants Ministerio de Ciencia e Innovaci?n PID2019-10454RB-I00/ AEI/10.13039/501100011033, Fondo de Investigaciones Sanitarias and COV20/ 01007E Proyecto Intramural Especial 201920E111 from Consejo Superior de Investigaciones Cient?ficas (to J.F.D.) and European Union H2020-MSCA-ITN-2019 860070 TUBINTRAIN grant (to J.F.D. and A.E.P.). We thank staff of the Smithsonian Marine Station for assistance with sample collection and extraction. We thank Wesley Yoshida (University of Hawaii at Manoa) for assistance with the 15N NMR experiments and Long H. Dang (UF Department of Medicine) for providing the HCT116 knockout cells. We thank Susan L. Mooberry (University of Texas Health Science Center at San Antonio) for support with the pharmacological studies; she acknowledges Greehey Endowment support. We thank John A. Beutler of the Molecular Targets Program at the National Cancer Institute for assistance with COMPARE analysis. We thank Ganader?a Fernando D?az for calf brains supply, and thank staff of beamline XALOC (ALBA, Cerdanyola del Vall?s, Spain) for their support. We thank Cora Petersen for her assistance with the cell proliferation studies. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = mar,
day = "2",
doi = "10.1073/pnas.2021847118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "9",
}