SirReal2

SirReal2
Clinical data
Drug class	Sirtuin 2 (SIRT2) inhibitor
Identifiers
	IUPAC name 2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[5-(naphthalen-1-ylmethyl)-1,3-thiazol-2-yl]acetamide;
CAS Number	709002-46-0;
PubChem CID	1096292;
ChemSpider	934777;
ChEMBL	ChEMBL3770903;
Chemical and physical data
Formula	C22H20N4OS2
Molar mass	420.55 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=CC(=NC(=N1)SCC(=O)NC2=NC=C(S2)CC3=CC=CC4=CC=CC=C43)C;
	InChI InChI=1S/C22H20N4OS2/c1-14-10-15(2)25-22(24-14)28-13-20(27)26-21-23-12-18(29-21)11-17-8-5-7-16-6-3-4-9-19(16)17/h3-10,12H,11,13H2,1-2H3,(H,23,26,27); Key:MENNDDDTIIZDDN-UHFFFAOYSA-N;

SirReal2 is a drug which acts as a potent and selective sirtuin 2 (SIRT2) inhibitor. It inhibits SIRT2 with an IC₅₀ of 140nM, and is selective over SIRT1, SIRT3 and SIRT5. It is used in research into cancer, inflammation and neurodegenerative disorders such as Parkinson's disease, and has led to the discovery of a number of related derivatives.^[1]^[2]^[3]^[4]^[5]^[6]^[7]

References

^ Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, et al. (February 2015). "Selective Sirt2 inhibition by ligand-induced rearrangement of the active site". Nature Communications. 6 6263. Bibcode:2015NatCo...6.6263R. doi:10.1038/ncomms7263. PMC 4339887. PMID 25672491.
^ Li Y, Zhang M, Dorfman RG, Pan Y, Tang D, Xu L, et al. (July 2018). "SIRT2 Promotes the Migration and Invasion of Gastric Cancer through RAS/ERK/JNK/MMP-9 Pathway by Increasing PEPCK1-Related Metabolism". Neoplasia. 20 (7): 745–756. doi:10.1016/j.neo.2018.03.008. PMC 6005814. PMID 29925042.
^ Spiegelman NA, Price IR, Jing H, Wang M, Yang M, Cao J, et al. (September 2018). "Direct Comparison of SIRT2 Inhibitors: Potency, Specificity, Activity-Dependent Inhibition, and On-Target Anticancer Activities". ChemMedChem. 13 (18): 1890–1894. doi:10.1002/cmdc.201800391. PMC 6402572. PMID 30058233.
^ Qu ZA, Ma XJ, Huang SB, Hao XR, Li DM, Feng KY, et al. (March 2020). "SIRT2 inhibits oxidative stress and inflammatory response in diabetic osteoarthritis". European Review for Medical and Pharmacological Sciences. 24 (6): 2855–2864. doi:10.26355/eurrev_202003_20649. PMID 32271403.
^ Scarano N, Abbotto E, Musumeci F, Salis A, Brullo C, Fossa P, et al. (May 2023). "Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors". International Journal of Molecular Sciences. 24 (11): 9363. doi:10.3390/ijms24119363. PMC 10253774. PMID 37298312.
^ Luo Y, Zhao H, Zhu J, Zhang L, Zha J, Zhang L, et al. (September 2023). "SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells". Cancer Medicine. 12 (18): 18901–18917. doi:10.1002/cam4.6480. PMC 10557894. PMID 37658623.
^ Ibrahim MA, Abdeljawaad KA, Abdelrahman AH, Arzumanyan G, Mekhemer GA, Abdelbacki AM, et al. (May 2025). "Hunting potential SIRT2 inhibitors towards cancer treatment: Drug repurposing, molecular dynamics, and binding energy computations". Biochemical and Biophysical Research Communications. 760 151701. Bibcode:2025BBRC..76051701I. doi:10.1016/j.bbrc.2025.151701. PMID 40158406.

[1] Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, et al. (February 2015). "Selective Sirt2 inhibition by ligand-induced rearrangement of the active site". Nature Communications. 6 6263. Bibcode:2015NatCo...6.6263R. doi:10.1038/ncomms7263. PMC 4339887. PMID 25672491.

[2] Li Y, Zhang M, Dorfman RG, Pan Y, Tang D, Xu L, et al. (July 2018). "SIRT2 Promotes the Migration and Invasion of Gastric Cancer through RAS/ERK/JNK/MMP-9 Pathway by Increasing PEPCK1-Related Metabolism". Neoplasia. 20 (7): 745–756. doi:10.1016/j.neo.2018.03.008. PMC 6005814. PMID 29925042.

[3] Spiegelman NA, Price IR, Jing H, Wang M, Yang M, Cao J, et al. (September 2018). "Direct Comparison of SIRT2 Inhibitors: Potency, Specificity, Activity-Dependent Inhibition, and On-Target Anticancer Activities". ChemMedChem. 13 (18): 1890–1894. doi:10.1002/cmdc.201800391. PMC 6402572. PMID 30058233.

[4] Qu ZA, Ma XJ, Huang SB, Hao XR, Li DM, Feng KY, et al. (March 2020). "SIRT2 inhibits oxidative stress and inflammatory response in diabetic osteoarthritis". European Review for Medical and Pharmacological Sciences. 24 (6): 2855–2864. doi:10.26355/eurrev_202003_20649. PMID 32271403.

[5] Scarano N, Abbotto E, Musumeci F, Salis A, Brullo C, Fossa P, et al. (May 2023). "Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors". International Journal of Molecular Sciences. 24 (11): 9363. doi:10.3390/ijms24119363. PMC 10253774. PMID 37298312.

[6] Luo Y, Zhao H, Zhu J, Zhang L, Zha J, Zhang L, et al. (September 2023). "SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells". Cancer Medicine. 12 (18): 18901–18917. doi:10.1002/cam4.6480. PMC 10557894. PMID 37658623.

[7] Ibrahim MA, Abdeljawaad KA, Abdelrahman AH, Arzumanyan G, Mekhemer GA, Abdelbacki AM, et al. (May 2025). "Hunting potential SIRT2 inhibitors towards cancer treatment: Drug repurposing, molecular dynamics, and binding energy computations". Biochemical and Biophysical Research Communications. 760 151701. Bibcode:2025BBRC..76051701I. doi:10.1016/j.bbrc.2025.151701. PMID 40158406.

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