Plinabulin, a marine-derived small-molecule, is BeyondSpring's lead asset and is currently in late-stage clinical development as an anticancer therapy in non-small cell lung cancer (NSCLC) and for the prevention of chemotherapy-induced neutropenia (CIN).
Click here for an illustrative video on Plinabulin's MOA.
Plinabulin binds to and affects the function of the protein tubulin within cells of the body, in a manner recently demonstrated to differ significantly from all other approved or advanced tubulin targeting agents. Tubulin aggregates or polymerizes inside cells to form strands called microtubules that have different functions indifferent cells. Therefore disrupting microtubules with Plinabulin has different effects in different cell types in the body. Moreover, even in the same cells, different microtubule targeting agents can have very different effects due to the differential binding to tubulin.
In dendritic cells of the immune system that capture and present foreign antigen to induce T-cells to attack and kill cancer cells expressing mutated proteins, microtubule targeting with Plinabulin activates a protein named GEF-H1 to boost the ability of dendritic cells to activate T-cells. This effect is thought to contribute towards the ability of Plinabulin to shrink tumors and increase patient survival. In tumor cells, in contrast, disrupting microtubules with Plinabulin reduces cell proliferation and causes cell suicide, including in KRAS wild type and KRAS mutant cancer cells. Importantly, while Plinabulin has very different effects on dendritic cells and tumor cells, both effects are thought to contribute towards the anti-cancer benefits of Plinabulin reported in the clinic.
In addition to anti-cancer benefits, clinical and nonclinical testing has demonstrated a dramatic positive effect of Plinabulin on chemotherapy-induced neutropenia (CIN), a major source of chemotherapy dose reductions and toxicity. The mechanism underlying the anti-CIN benefits of Plinabulin are distinct from the standard of care for CIN, G-CSF based therapeutics. Clinical and nonclinical data indicate Plinabulin boosts the number of primitive stem/progenitor cells in the bone marrow that are the source of mature immune cells in the blood, including neutrophils. The effect of microtubule targeting on stem/progenitor cell number may therefore significantly contribute towards the anti-CIN benefits of Plinabulin. Importantly, the impressive and unique profile of Plinabulin clinical benefits goes beyond anti-cancer and anti-CIN; Plinabulin also shows evidence of alleviating chemotherapy-induced thrombocytopenia (platelets), and near prevention of bone pain caused by G-CSF based therapy when administered in combination for the treatment of CIN. The cells affected by Plinabulin and responsible for the dramatic reduction in G-CSF induced bone pain are at present unknown.
This highly differentiated mechanism of action is published at Cell journals including Chem and Cell Reports. Links below.