Plinabulin

Plinabulin
Names
	IUPAC name (3Z,6Z)-3-Benzylidene-6-{[5-(2-methyl-2-propanyl)-1H-imidazol-4-yl]methylene}-2,5-piperazinedione
Identifiers
CAS Number	714272-27-2 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:177413;
ChemSpider	8125252;
KEGG	D09655;
PubChem CID	9949641;
UNII	986FY7F8XR ;
CompTox Dashboard (EPA)	DTXSID201031311 ;
	InChI 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;
	SMILES O=C3/C(=C/c1nc[nH]c1C(C)(C)C)NC(=O)C(=C\c2ccccc2)\N3;
Properties
Chemical formula	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). Infobox references

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

^ "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.
^ 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.
^ "Nivolumab and Plinabulin in Treating Patients With Stage IIIB-IV, Recurrent, or Metastatic Non-small Cell Lung Cancer".
^ Nivolumab in Combination With Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC).
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

[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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