YC8-02

YC8-02
Clinical data
Drug class	SIRT2/3 inhibitor
Identifiers
	IUPAC name 2-[[(2S)-1-(3-hydroxyanilino)-1-oxo-6-(tetradecanethioylamino)hexan-2-yl]amino]ethyl-triphenylphosphanium;
PubChem CID	177378251;
ChEMBL	ChEMBL5595757;
Chemical and physical data
Formula	C46H63N3O2PS
Molar mass	753.06 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCCCCCCCCCCCCC(=S)NCCCC[C@@H](C(=O)NC1=CC(=CC=C1)O)NCC[P+](C2=CC=CC=C2)(C3=CC=CC=C3)C4=CC=CC=C4;
	InChI InChI=1S/C46H62N3O2PS/c1-2-3-4-5-6-7-8-9-10-11-21-34-45(53)48-35-23-22-33-44(46(51)49-39-25-24-26-40(50)38-39)47-36-37-52(41-27-15-12-16-28-41,42-29-17-13-18-30-42)43-31-19-14-20-32-43/h12-20,24-32,38,44,47H,2-11,21-23,33-37H2,1H3,(H2-,48,49,50,51,53)/p+1/t44-/m0/s1; Key:RIVWUGLXBPHZGR-SJARJILFSA-O;

YC8-02 is a drug which acts as a potent inhibitor of the enzymes sirtuin 2 (SIRT2) and sirtuin 3 (SIRT3). It was developed from an older SIRT2 selective inhibitor thiomyristoyl, but substituted with a triphenylphosphine group which increases affinity to SIRT3 and selectively targets uptake into mitochondria. It is still relatively selective for SIRT2 with an IC₅₀ of 62nM at SIRT2 vs 530nM at SIRT3, but this still makes it one of the most potent SIRT3 inhibitors currently available. In animal studies it is useful for the treatment of certain forms of blood cancer such as lymphoma and leukemia.^[1]^[2]^[3]

References

^ Li M, Chiang YL, Lyssiotis CA, Teater MR, Hong JY, Shen H, et al. (June 2019). "Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis". Cancer Cell. 35 (6): 916–931.e9. doi:10.1016/j.ccell.2019.05.002. PMC 7534582. PMID 31185214.
^ Jana S, Shang J, Hong JY, Fenwick MK, Puri R, Lu X, et al. (September 2024). "A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma". Journal of Medicinal Chemistry. 67 (17): 15428–15437. doi:10.1021/acs.jmedchem.4c01053. PMID 39191393.
^ O'Brien C, Ling T, Berman JM, Culp-Hill R, Reisz JA, Rondeau V, et al. (September 2023). "Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity". Haematologica. 108 (9): 2343–2357. doi:10.3324/haematol.2022.281894. PMID 37021547.

[1] Li M, Chiang YL, Lyssiotis CA, Teater MR, Hong JY, Shen H, et al. (June 2019). "Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis". Cancer Cell. 35 (6): 916–931.e9. doi:10.1016/j.ccell.2019.05.002. PMC 7534582. PMID 31185214.

[2] Jana S, Shang J, Hong JY, Fenwick MK, Puri R, Lu X, et al. (September 2024). "A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma". Journal of Medicinal Chemistry. 67 (17): 15428–15437. doi:10.1021/acs.jmedchem.4c01053. PMID 39191393.

[3] O'Brien C, Ling T, Berman JM, Culp-Hill R, Reisz JA, Rondeau V, et al. (September 2023). "Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity". Haematologica. 108 (9): 2343–2357. doi:10.3324/haematol.2022.281894. PMID 37021547.

[1]

[2]

[3]

See also

References