In the Chem article, titled, “Structure, Thermodynamics and Kinetics of Plinabulin Binding to Two Tubulin Isotypes,”1 researchers utilizing x-ray crystallography and thermodynamics calculations demonstrated that Plinabulin as a NCE (new chemical entity) is differentiated from other tubulin-binding agents in both its binding site and the kinetics of the binding. The research also provides evidence that this binding may explain the beneficial efficacy and superior safety profile found with Plinabulin in the clinic, compared to other agents that bind to a nearby colchicine site in tubulin, such as C4AP (combretastatin-A4) or colchicine.
The lead authors of the Chem article include:
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Dr.
Andrea Cavalli of Istituto Italiano di Tecnologia (IIT) andUniversity of Bologna -
Dr.
Michel Steinmetz ofPaul Scherrer Institute (PSI) and theUniversity of Basel -
Drs.
Lan Huang ,James R. Tonra andG. Kenneth Lloyd ofBeyondSpring
In addition to the Chem publication, data on Plinabulin’s ability to positively affect the body’s immune mechanism was published in Cell Reports, titled, “GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses.”2 The Cell Reports article demonstrates that Plinabulin destabilizes microtubule and releases immune defense protein GEF-H1, a critical signaling protein for dendritic cell (DC) maturation, antigen cross-presentation and effective priming of CD8 T cells. In the absence of GEF-H1, anti-tumor immunity is hindered. Researchers noted that, in cancer patients, high expression of the GEF-H1 immune gene signature is associated with prolonged survival. Plinabulin is among the most potent tubulin targeted agents for maturing DCs. This highlights Plinabulin’s potential as an ideal partner for combination immuno-oncology approaches seeking to overcome the limitations of checkpoints in treating certain cancers. This finding significantly contributes towards BeyondSpring’s understanding of the durable anti-cancer effects demonstrated to date in nonclinical and clinical testing with Plinabulin.
The lead authors of the Cell Reports article include:
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Dr.
Alfred Zippelius of University Hospital Basel andUniversity of Basel -
Dr.
Hans-Christian Reinecker ofMassachusetts General Hospital ,Harvard Medical School -
Dr.
Abhishek Kashyap of University Hospital Basel andUniversity of Basel andMassachusetts General Hospital ,Harvard Medical School -
Dr.
Michel Steinmetz of PSI and theUniversity of Basel
“This journey from the ‘bedside’ back to the ‘benchside’ to uncover Plinabulin's mechanism represents more than five years of international collaborative work with leading institutions. We are grateful to our collaborators and this important recognition by the scientific community that Plinabulin is a first-in-class clinical asset for cancer treatment through an important immune mechanism,” said Dr.
References:
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La
Sala , G, Olieric, N, Sharma, A, Viti, F, deAsis Balaguer Perez , F, Huang, L, Tonra JR, Lloyd GK, Decherchi, S, Diaz, JF, Steinmetz, MO and Cavalli, A (2019) Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes. Chem 5:1-18. https://www.cell.com/chem/fulltext/S2451-9294(19)30391-2 -
Kashyap, AS, Fernandez-Rodriguez, L, Zhao, Y,
Monaco , G, Trefny, MP, Yoshida, N, Martin, K, Sharma, A, Olieric N, Shah, P, Stanczak, M, Kirchhammer, N, Park, S-M, Wieckowski, S, Laubil, H, Zagani, R, Kasenda, B, Steinmetz, MO, Reinecker, H-C and Zippelius, A (2019) GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses. Cell Reports 28: 3367-3380.
https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31105-2
About
About Plinabulin
Plinabulin, BeyondSpring’s lead asset, is a marine-derived small molecule that sequesters tubulin heterodimers in a differentiated manner from other agents in this class. Plinabulin is currently in late-stage clinical development to increase overall survival in cancer patients, as well as to alleviate chemotherapy-induced neutropenia (CIN). The anticancer benefits of Plinabulin have been associated with positive effects on antigen presenting cells and T-cell activation, as well as to the direct killing of cancer cells. Plinabulin’s CIN data highlights the ability to positively affect the number of hematopoietic stem / progenitor cells (HSPCs), or lineage-/cKit+/Sca1+ (LSK) cells in mice. Effects on HSPCs could explain the ability of Plinabulin to not only treat CIN but also to reduce chemotherapy-induced thrombocytopenia and increase circulating CD34+ cells in patients.
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