GSK591

Biological Activity

gsk591 is a prmt5 inhibitor.protein arginine methyltransferase-5 (prmt5) is found to have a critical role in various cellular processes such as tumorigenesis, and the overexpression of prmt5 is observed in cell lines and primary patient samples derived from lymphomas, especially mantle cell lymphoma.

Biochem/physiol Actions

GSK591 is also known as 2-(cyclobutylamino)-N-[(2S)-3-(3,4-dihydro-2(1H)-isoquinolinyl)-2-hydroxypropyl]-4-pyridinecarboxamide, EPZ015866 and GSK3203591. It prevents the systemic arginine methylation of SmD3 (small nuclear ribonucleoprotein).

in vitro

by further optimization of epz015666, an extremely potent in vitro tool analog of epz015666, gsk591, was identified. gsk591 was found to maintain excellent selectivity against other pmt enzymes, which was similar to that of epz015666. in addition, gsk591 was shown to be an extremely potent compound suitable for in vitro studies with excellent hlm stability [1].

in vivo

in mouse pk studies, gsk591, epz015666 and their analogs showed moderate to high plasma clearance and a wide range of oral bioavailability. the volume of distribution values in these studies were from 0.6 to 45 l/kg. further pk studies demonstrated that at 100 mg/kg in mouse, the unbound plasma concentration was equivalent to or above the ic90 for a period of 12 h, therefore, indicating that the bid dosing regimen of epz015666 was able to effectively inhibit prmt5 in vivo [1].

References

[1] duncan kw et al. structure and property guided design in the identification of prmt5 tool compound epz015666. acs med chem lett. 2015 dec 2;7(2):162-6.