Anticancer agents : “No SIR!”

07 Dec 2015 NUS scientists have discovered a new chemotype with sirtuin inhibitory activity.

Sirtuins is a family of evolutionary-conserved enzymes whose important roles in diverse and interrelated cellular processes such as stress response, gene expression, DNA damage repair and metabolism have always been somewhat controversial. There are questions relating to the physiological roles of sirtuins which have yet to be satisfactorily addressed. For example, are sirtuins as influential as claimed, affecting a gamut of bodily processes that range from aging to malignancies? Activators and inhibitors of sirtuins have their detractors as well.

Notably, inhibition of sirtuins is a double-edged sword as sirtuins have bifurcated roles as tumour suppressors and tumour promoters, depending on the state of malignancy and the tumor environment. A team led by Prof GO Mei Lin from the Department of Pharmacy in NUS showed that inhibition of sirtuin 2, a subfamily located in the cytosol of cells, by a tetrahydropyridoindole analog resulted in an accumulation of acetylated p53 in two cancer cell lines. When maintained in its acetylated state, p53 is protected from proteasomal degradation and hence able to exercise its tumor suppressive properties. On the in vitro assay, the same compound selectively inhibited sirtuin 2 at an IC50 of 4 µM. Significantly, inhibition of sirtuin 2 mediated p53 deacetylation in cancer cells was observed at the same concentration range. In its activated and stabilized acetylated state, p53 is well positioned to increase transcription of genes involved in apoptotic cell death, and this was indeed observed for cancer cells exposed to the tetrahydropyridoindole analog. Molecular docking showed that the target compound was positioned at sites in sirtuin 2 that were normally occupied by the cofactor NAD+ and the acetylated substrate.

Taken together, they have identified a new chemotype associated with low micromolar selective inhibition of sirtuin 2. Sirtuin inhibition was functionally relevant in a cell based context and apoptosis was observed in cancer cells treated with the target compound.

GoML Dec                 

Figure shows (A) Structural modification of the tetrahydropyridoindole analogs led to an increase in sirtuin 2 inhibitory activity. Compound 18 was the most promising analog identified. (B) Docking pose of compound 18 in the NAD+ binding pocket of sirtuin 2 (PDB 3ZGV). [Image credit: GO Mei Lin]



Yang TM, Chen X, Jin HX, Sethi G, ML Go. “Functionalized tetrahydro-1H-pyrido[4,3-b]indoles: A novel chemotype with Sirtuin 2  inhibitory activity.“ European Journal of Medicinal Chemistry 92 (2015) 145.