T-5224

T-5224
Clinical data
Other names	T5224; R-7277; R7277; T-5226; T5226
Routes of; administration	Oral
Drug class	Transcription factor AP-1 inhibitor
ATC code	None;
Identifiers
	IUPAC name 3-[5-(4-cyclopentyloxy-2-hydroxybenzoyl)-2-[(3-oxo-1,2-benzoxazol-6-yl)methoxy]phenyl]propanoic acid;
CAS Number	530141-72-1;
PubChem CID	23626877;
DrugBank	DB05998;
ChemSpider	25069717;
UNII	3Z4EGU4HKZ;
ChEMBL	ChEMBL3222137;
Chemical and physical data
Formula	C29H27NO8
Molar mass	517.534 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CCC(C1)OC2=CC(=C(C=C2)C(=O)C3=CC(=C(C=C3)OCC4=CC5=C(C=C4)C(=O)NO5)CCC(=O)O)O;
	InChI InChI=1S/C29H27NO8/c31-24-15-21(37-20-3-1-2-4-20)8-10-22(24)28(34)19-6-11-25(18(14-19)7-12-27(32)33)36-16-17-5-9-23-26(13-17)38-30-29(23)35/h5-6,8-11,13-15,20,31H,1-4,7,12,16H2,(H,30,35)(H,32,33); Key:DALCQQSLNPLQFZ-UHFFFAOYSA-N;

T-5224 is a small-molecule c-Fos/activator protein 1 (AP-1) inhibitor which was under development for the treatment of rheumatoid arthritis but was never marketed.^[1]^[2]^[3] It is taken orally.^[1] The drug was under development by Toyama Chemical.^[1]^[2] It reached phase 2 clinical trials prior to the discontinuation of its development.^[1]^[2]

T-5224 has been found to selectively inhibit FOS-containing AP-1 complexes.^[4]^[5]^[3] An analogous kind of approach might be useful for targeting a subset of ΔFosB-associated complexes to treat conditions like addiction.^[4] The activity of T-5224 itself against ΔFosB is unknown.^[5]

References

1 2 3 4 5 "T 5224". AdisInsight. Springer Nature Switzerland AG. 29 October 2018. Retrieved 6 March 2026.
1 2 3 "Delving into the Latest Updates on T-5224 with Synapse". Synapse. PatSnap. 7 June 2025. Retrieved 6 March 2026.
1 2 Aikawa Y, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, et al. (July 2008). "Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1". Nature Biotechnology. 26 (7): 817–823. doi:10.1038/nbt1412. PMID 18587386.
1 2 Robison AJ, Nestler EJ (February 2022). "ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression". ACS Chemical Neuroscience. 13 (3): 296–307. doi:10.1021/acschemneuro.1c00723. PMC 8879420. PMID 35020364. As we have described, ΔFOSB is expressed in many different cell types and tissues in response to stimuli both natural and artificial, and its functions range from mediating responses to psychotropic drugs, to controlling stress susceptibility vs resilience, to facilitating learning and memory, to transforming bone cells to drive tumor growth, and beyond. As such, ΔFOSB has often been questioned as a viable target for therapeutic intervention in the many disease states with which it is associated due to presumptive concerns of side effects in any of these diverse areas of function. However, it has become apparent that TFs with a similar diversity of functions and gene targets are viable pharmacological targets for the treatment of disease.128 One of the clearest examples of this advance has been the selective inhibition of FOS-containing AP1 complexes by the drug T-5224. This compound has been proven to be effective in reversing arthritis and spinal cartilage degeneration in preclinical mouse models,35,36 and Toyoma Chemical has entered this compound in Phase II trials for the treatment of rheumatoid arthritis.
1 2 Wang Y, Cesena TI, Ohnishi Y, Burger-Caplan R, Lam V, Kirchhoff PD, et al. (July 2012). "Small molecule screening identifies regulators of the transcription factor ΔFosB". ACS Chemical Neuroscience. 3 (7): 546–556. doi:10.1021/cn3000235. PMC 3399579. PMID 22860224. Recent studies show that a number of transcription factors can be regulated with small molecules.30,31 [...] While small molecule inhibitors of c-Fos-containing AP-1 complexes are known, such as curcumin,35 tanshinone IIA,36 and nordihydroguaiaretic acid,37 these are not active against ΔFosB or JunD-containing species (tested up to 100 μM, results not shown). A benzophenone derivative in preclinical trials to resolve arthritis, T-5224, also inhibits c-Fos and c-Jun-containing AP-1 activity, though the mechanism of action and its activity against ΔFosB are not known.38

[AdisInsight-1] 1 2 3 4 5 "T 5224". AdisInsight. Springer Nature Switzerland AG. 29 October 2018. Retrieved 6 March 2026.

[Synapse-2] 1 2 3 "Delving into the Latest Updates on T-5224 with Synapse". Synapse. PatSnap. 7 June 2025. Retrieved 6 March 2026.

[Aikawa_2008-3] 1 2 Aikawa Y, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, et al. (July 2008). "Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1". Nature Biotechnology. 26 (7): 817–823. doi:10.1038/nbt1412. PMID 18587386.

[Robison_2022-4] 1 2 Robison AJ, Nestler EJ (February 2022). "ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression". ACS Chemical Neuroscience. 13 (3): 296–307. doi:10.1021/acschemneuro.1c00723. PMC 8879420. PMID 35020364. As we have described, ΔFOSB is expressed in many different cell types and tissues in response to stimuli both natural and artificial, and its functions range from mediating responses to psychotropic drugs, to controlling stress susceptibility vs resilience, to facilitating learning and memory, to transforming bone cells to drive tumor growth, and beyond. As such, ΔFOSB has often been questioned as a viable target for therapeutic intervention in the many disease states with which it is associated due to presumptive concerns of side effects in any of these diverse areas of function. However, it has become apparent that TFs with a similar diversity of functions and gene targets are viable pharmacological targets for the treatment of disease.128 One of the clearest examples of this advance has been the selective inhibition of FOS-containing AP1 complexes by the drug T-5224. This compound has been proven to be effective in reversing arthritis and spinal cartilage degeneration in preclinical mouse models,35,36 and Toyoma Chemical has entered this compound in Phase II trials for the treatment of rheumatoid arthritis.

[Wang_2012-5] 1 2 Wang Y, Cesena TI, Ohnishi Y, Burger-Caplan R, Lam V, Kirchhoff PD, et al. (July 2012). "Small molecule screening identifies regulators of the transcription factor ΔFosB". ACS Chemical Neuroscience. 3 (7): 546–556. doi:10.1021/cn3000235. PMC 3399579. PMID 22860224. Recent studies show that a number of transcription factors can be regulated with small molecules.30,31 [...] While small molecule inhibitors of c-Fos-containing AP-1 complexes are known, such as curcumin,35 tanshinone IIA,36 and nordihydroguaiaretic acid,37 these are not active against ΔFosB or JunD-containing species (tested up to 100 μM, results not shown). A benzophenone derivative in preclinical trials to resolve arthritis, T-5224, also inhibits c-Fos and c-Jun-containing AP-1 activity, though the mechanism of action and its activity against ΔFosB are not known.38

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