GSK3685032 is a non-time-dependent, highly selective enzymatic inhibitor of DNA methyltransferase (DNMT1) with IC50 of 0.036 μM, and over 2500-fold more selective than DNMT3A/3L and DNMT3B/3L.
GSK3685032 engages DNMT1 specifically in both biochemical and cellular contexts, and its selective inhibition of DNMT1 slows cancer cell growth. GSK3685032 also induces DNA hypomethylation and gene activation.[1]
In mice, GSK3685032 exhibits low clearance, a moderate volume of distribution, and a blood half-life >1.8 h with dose-proportional exposure from 1 to 45 mg/kg, higher doses of GSK3685032 show reductions in neutrophils and red blood cells, these doses showing markedly greater DNA hypomethylation and tumor growth inhibition/regression.[1]
[1] Melissa B. Pappalardi,et al. Nat Cancer. 2021 Oct; 2(10): 1002–1017.