MOAs of Anti-cancer
As a tubulin depolymerizing agent, Plinabulin works via multiple mechanisms of action to target and alter the tumor microenvironment:
- Immune enhancing effects
- Tumor cell apoptosis via activation of JNK pathway
- Selectively targeting tumor vasculature
Immune Enhancing Effects via Dendritic Cell Maturation
It is believed that Plinabulin targets the microtubules of the dendritic cells, resulting in a potent maturation of dendritic cells, which then generates an amplified immune system response to fight disease. (Y. Wang et al.)1 (A.E. Prota et. al.)2
More specifically, as a tubulin depolymerizing agent, Plinabulin belongs to a class of compounds that induce the maturation of dendritic cells – which are antigen-presenting cells that when mature, directly activate and control immune system cell responses – as shown by up-regulating specific maturation biomarkers and releasing specific cytokines. Mature dendritic cells migrate to lymph nodes, where they present tumor antigen to T-cells, which proliferate and infiltrate into the tumor. Plinabulin has been shown to act synergistically in tumor growth inhibition and survival extension with downstream immune modulators, such as immune checkpoint antibodies (PD-1 Ab and CTLA-4 Ab). (K. Martin et al.)3
Tumor Cell Apoptosis via JNK Pathway
In cancer cells, Plinabulin disrupts microtubules critical for cell division, leading to apoptosis via the activated JNK pathway. The sustained activation of JNK, in conjunction with caspase activation and PARP cleavage, is independent of RAS mutation. The therapeutic implication is currently under investigation. ( A.V. Singh et al.)4
Anti-Angiogenesis and Targeting Existing Vasculature
Plinabulin is a tubulin depolymerizing agent that destabilizes the tubulin network in endothelial cells in the tumor, resulting in the selective collapse of established vasculature, blockage of blood flow and inhibition of new blood vessel formation (angiogenesis), leading to subsequent tumor necrosis (death). Anti-tumor activity can be achieved with Plinabulin alone or in combination with cytotoxic agents. (B. Nicholson et al.)5( A.V. Singh et al.)
- Wang et al., Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery, FEBS J. Vol. 283, No. 1, pp. 102 – 11, 2016.
- E. Prota et. al., Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agent, Science, Vol. 339, No. 6119, pp. 587 – 590, 2013.
- Martin et al., The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity, Cancer Immunology, Immunotherapy, Vol. 63, No. 9, pp. 925 – 938, 2014.
- V. Singh et al., A novel vascular disrupting agent plinabulin triggers JNK-mediated apoptosis and inhibits angiogenesis in multiple myeloma cells, Blood, Vol. 117, No. 21, pp. 5692-1700, 2011.Access through PubMed
- B. Nicholson et al., NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent, Anticancer Drugs, 17(1):25-31, 2006.
- Mira et al., Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton, Nature Cell Biology, 4, 294-301(2002)