Topic
Plinabulin
About: Plinabulin is a research topic. Over the lifetime, 85 publications have been published within this topic receiving 1144 citations. The topic is also known as: Plinabulin.
Papers
TL;DR: These studies provide a solid structural basis for developing new anti‐cancer agents for the colchicine binding site and show that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure‐based drug design.
Abstract: Microtubules are dynamic assemblies of αβ-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site. Database The atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes 5CA0, 5CA1, 5C8Y and 5CB4, respectively.
218 citations
TL;DR: Phenylahistin is a fungal diketopiperazine metabolite consisting of L -phenylalanine and isoprenylated dehydrohistidine and it showed an inhibitory activity on the cell cycle progression of P388 cells in the G2/M phase.
153 citations
TL;DR: More potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group are developed, which could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.
Abstract: Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine “phenylahistin” (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activi...
104 citations
TL;DR: Phenylahistin exhibited antitumor activity against 8 tumor cell lines with IC50 values ranging from 1.8 x 10 (-7) to 3.7 x 10(-6), while (+)-phenylahistsin exhibited 33-100-fold less potent activity than (-)-phenylon did.
Abstract: Phenylahistin is a new cell cycle inhibitor produced by Aspergillus ustus. Since phenylahistin was produced as a scalemic mixture of (-)-phenylahistin and its enantiomer, we separated each enantiomer and evaluated their antitumor activity in vitro. (-)-Phenylahistin exhibited antitumor activity against 8 tumor cell lines with IC50 values ranging from 1.8×10-7 to 3.7×10-6, while (+)-phenylahistin exhibited 33-100-fold less potent activity than (-)-phenylahistin did. (-)-Phenylahistin also showed antitumor activity against P388 leukemia and Lewis lung carcinoma cells in vivo.
98 citations
TL;DR: The combination of full doses of plinabulin and docetaxel is tolerable and with encouraging antitumor activity, this supported further development of this combination.
Abstract: Background Plinabulin (NPI-2358) is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature producing anti-tumor activity alone or in combination with cytotoxic agents. The objective of this study was to assess the recommended Phase 2 dose (RP2D) of plinabulin combined with docetaxel. Patients and Methods Patients received 75 mg/m2 docetaxel on day 1 and plinabulin on days 1 and 8 intravenously in 21 day cycles. Plinabulin was escalated from the biologically effective dose (BED) of 13.5 mg/m2 to the standard single agent dose of 30 mg/m2 using a “3+3” design. Results Thirteen patients were enrolled. Adverse events were consistent with those of both agents alone. Fatigue, pain, nausea, diarrhea and vomiting were the most common events. One dose limiting toxicity of nausea, vomiting, dehydration and neutropenia occurred. The RP2D was 30 mg/m2 of plinabulin with 75 mg/m2 docetaxel. Pharmacokinetics did not indicate drug-drug interactions. Of the 8 patients with NSCLC evaluable for response, 2 achieved a partial response and 4 demonstrated lesser decreases in tumor measurements. Conclusions The combination of full doses of plinabulin and docetaxel is tolerable. With encouraging antitumor activity, this supported further development of this combination.
84 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 9 |
| 2020 | 9 |
| 2019 | 11 |
| 2018 | 9 |
| 2017 | 11 |
| 2016 | 11 |