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 Plinabulin

NPI-2358 is a synthetic analog of NPI-2350, a natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different from the colchicine-binding site agents reported to date, NPI-2358 binds to the colchicine-binding site of tubulin. NPI-2358 has potent in-vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles. In addition, when evaluated in proliferating human umbilical vein endothelial cells (HUVECs), concentrations as low as 10 nmol/l NPI-2358 induced tubulin depolymerization within 30 min. Furthermore, NPI-2358 dose dependently increases HUVEC monolayer permeability--an in-vitro model of tumor vascular collapse. NPI-2358 was compared with three tubulin-depolymerizing agents with vascular-disrupting activity: colchicine, vincristine and combretastatin A-4 (CA4). Results showed that the activity of NPI-2358 in HUVECs was more potent than either colchicine or vincristine; the profile of CA4 approached that of NPI-2358. Altogether, our data show that NPI-2358 is a potent anti-tumor agent which is active in MDR tumor cell lines, and is able to rapidly induce tubulin depolymerization and monolayer permeability in HUVECs. These data warrant further evaluation of NPI-2358 as a vascular-disrupting agent in vivo. see http://www.ncbi.nlm.nih.gov/pubmed/16317287.

NPI-2358 is  currently in clinical development for the treatment of cancer by Nereus. Initial results from a single-agent Phase 1 trial in various tumor types indicate NPI-2358 has a favorable safety profile, including cardiac safety. It is also being evaluated in a Phase 1b study in combination with docetaxel for the treatment of non-small cell lung cancer. NPI-2358 is one of over 200 synthetic analogues that were prepared following the discovery of the compound Halimide isolated from a marine fungus. In preclinical models of cancer, including lung, breast, sarcoma, colon and prostate, NPI-2358 demonstrated potent and selective anti-tumor effects in combination with docetaxel and other oncology therapies, as well as single-agent efficacy in a number of orthotopic models. NPI-2358 interacts with soluble beta-tubulin and prevents the polymerization of tubulin without altering dynamic microtubule function of formed microtubules. As demonstrated in preclinical testing, this target profile results in a highly specific nanomolar cytotoxicity while reducing the side effects seen in first-generation VDAs due to cardiotoxicity, hemodynamic changes and neuropathies. see news from medicalnewstoday.com.

Current developer:  Nereus Pharmaceuticals Inc。

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