Plinabulin

Last updated
Plinabulin
Plinabulin.svg
Names
IUPAC name
(3Z,6Z)-3-Benzylidene-6-{[5-(2-methyl-2-propanyl)-1H-imidazol-4-yl]methylene}-2,5-piperazinedione
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C19H20N4O2/c1-19(2,3)16-13(20-11-21-16)10-15-18(25)22-14(17(24)23-15)9-12-7-5-4-6-8-12/h4-11H,1-3H3,(H,20,21)(H,22,25)(H,23,24)/b14-9-,15-10-
    Key: UNRCMCRRFYFGFX-TYPNBTCFSA-N
  • InChI=1/C19H20N4O2/c1-19(2,3)16-13(20-11-21-16)10-15-18(25)22-14(17(24)23-15)9-12-7-5-4-6-8-12/h4-11H,1-3H3,(H,20,21)(H,22,25)(H,23,24)/b14-9-,15-10-
    Key: UNRCMCRRFYFGFX-TYPNBTCFBU
  • O=C3/C(=C/c1nc[nH]c1C(C)(C)C)NC(=O)C(=C\c2ccccc2)\N3
Properties
C19H20N4O2
Molar mass 336.395 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Plinabulin (provisional name BPI-2358, formerly NPI-2358) is a small molecule under development by BeyondSpring Pharmaceuticals, and has completed a world-wide Phase 3 clinical trial for non-small cell lung cancer. [1] Plinabulin is being investigated for the reduction of chemotherapy-induced neutropenia [2] and for anti-cancer effects in combination with immune checkpoint inhibitors [3] [4] and in KRAS mutated tumors. [5]

Plinabulin blocks the polymerization of tubulin in a unique manner, resulting in multi-factorial effects including an enhanced immune-oncology response, [6] [7] [8] activation of the JNK pathway [9] and disruption of the tumor blood supply.

References

  1. ↑ "Completed: Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC (DUBLIN-3), Phase Three". clinicaltrials.gov. 2021-05-23. Retrieved 2024-07-19.
  2. ↑ Heist, R.S.; Aren, O.R.; Mita, A.C.; Polikoff, J.; Bazhenova, L.; Lloyd, G.K.; Mikrut, W.; Reich, W.; Spear, M.A.; Huang, L. (2014). Randomized Phase 2 Trial of Plinabulin (NPI-2358) Plus Docetaxel in Patients with Advanced Non-Small Lung Cancer (NSCLC). J Clin Oncol 32:5s.
  3. ↑ "Nivolumab and Plinabulin in Treating Patients With Stage IIIB-IV, Recurrent, or Metastatic Non-small Cell Lung Cancer".
  4. ↑ Nivolumab in Combination With Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC).
  5. ↑ Lloyd, G.K.; Du, L.; Lee, G.; Dalsing-Hernandez, J.; Kotlarczyk, K.; Gonzalez, K.; Nawrocki, S.; Carew, J.; Huang, L. (October 5–9, 2015). Activity of Plinabulin in Tumor Models with Kras Mutations. Proceedings of the International Conference on Molecular Targets and Cancer Therapeutics. Boston MA.
  6. ↑ Kashyap, Abhishek S.; Fernandez-Rodriguez, Laura; Zhao, Yun; Monaco, Gianni; Trefny, Marcel P.; Yoshida, Naohiro; Martin, Kea; Sharma, Ashwani; Olieric, Natacha; Shah, Pankaj; Stanczak, Michal; Kirchhammer, Nicole; Park, Sung-Moo; Wieckowski, Sebastien; Laubli, Heinz; Zagani, Rachid; Kasenda, Benjamin; Steinmetz, Michel O.; Reinecker, Hans-Christian; Zippelius, Alfred (September 2019). "GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses". Cell Reports. 28 (13): 3367–3380.e8. doi:10.1016/j.celrep.2019.08.057. PMC   6876861 . PMID   31553907.
  7. ↑ Natoli, Marina; Herzig, Petra; Pishali Bejestani, Elham; Buchi, Melanie; Ritschard, Reto; Lloyd, G. Kenneth; Mohanlal, Ramon; Tonra, James R.; Huang, Lan; Heinzelmann, Viola; Trüb, Marta; Zippelius, Alfred; Kashyap, Abhishek S. (3 March 2021). "Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity". Frontiers in Oncology. 11. doi: 10.3389/fonc.2021.644608 . PMC   7966525 . PMID   33747968.
  8. ↑ La Sala, Giuseppina; Olieric, Natacha; Sharma, Ashwani; Viti, Federica; de Asis Balaguer Perez, Francisco; Huang, Lan; Tonra, James R.; Lloyd, G. Kenneth; Decherchi, Sergio; Díaz, José Fernando; Steinmetz, Michel O.; Cavalli, Andrea (November 2019). "Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes". Chem. 5 (11): 2969–2986. doi:10.1016/j.chempr.2019.08.022. hdl: 10261/198993 .
  9. ↑ Singh, A.V.; Bandi, M.; Raje, N.; Richardson, P.; Palladino, M.A.; Chauhan, D.; Anderson, K. (2011). "A Novel Vascular Disrupting Agent Plinabulin Triggers JNK-Mediated Apoptosis and Inhibits Angiogenesis in Multiple Myeloma Cells". Blood. 117 (21): 5692–5700. doi:10.1182/blood-2010-12-323857. PMC   3110026 . PMID   21454451.
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