epz031686 is the first smyd3 inhibitor.set and mynd domain containing 3 (smyd3), a lysine methyltransferase (kmt) expressed at high levels in a number of different cancer histologies, is reported to be associated with a poor clinical prognosis.
epz031686 was the first smyd3 inhibitor found to show double-digit nanomolar cellular activity. in addition, epz031686 displayed noncompetitive inhibition to both sam and mekk2 with a ki = 1.2 and 1.1 nm, respectively. moreover, epz031686 showed less than 30% inhibition against 16 histone methyltransferase targets at a 10 μm [1].
male mice i.v. administered a single dose of epz031686 at 1 mg/kg showed a moderate clearance of 27 ml/min/kg, which was in very good agreement with the microsomal data, with a volume of distribution at steady state of 2.3 l/kg, translating to a terminal half-life of 1.7 h. around 20% of the administered dose was excreted unchanged in urine after 24 h, equivalent to a renal clearance of 5.3 ml/min/kg. bioavailability of 48 and 69 was observed at 5 and 50 mg/kg, respectively, resulting in the epz031686 unbound blood concentration remaining above the smyd3 ic50 value for more than 12 h after a 50 mg/kg p.o. administration [1].
[1] mitchell lh et al. novel oxindole sulfonamides and sulfamides: epz031686, the first orally bioavailable small molecule smyd3 inhibitor. acs med chem lett. 2015 aug 27;7(2):134-8.
