ARUK2001607

ARUK2001607 is a PI5P4Kγ (PIP4K2C) inhibitor with good potency (79.4 nM) in an enzyme assay conducted on an activated PI5P4Kγ variant (PI5P4Kγ+, see DOI: 10.1021/acs.jmedchem.2c01693). Affinity for the WT enzyme was confirmed in a lipid kinase binding assay (Kd = 7.1 nM) and in cells using a thermal stabilization assay (IC50 ~250 nM). No functional data/effect on downstream signaling reported for complementary confirmation of cellular activity. High selectivity against the isoforms PI5P4Kα and PI5P4Kβ was shown in enzyme assays and kinome selectivity was confirmed @10µM in a 140 kinase panel. Isoform selectivity in cells and effect on downstream signaling was not assessed. The compound showed a clean profile in a Cerep safety panel (24 cellular and nuclear receptors, 10 enzymes and uptake receptors, 6 ion channels). ARUK2001607 is brain penetrant and shows a short-moderate half-life after ip dosing in mice (5 mg/kg , t1/2 = 0.74 h). Oral bioavailability is unknown. No inactive control is provided. For cell experiments, I recommend using the compound in conjunction with an orthogonal probe like SGC-PI5P4Kg/MYLK-1 + negative control SGC-PI5P4Kγ/MYLK4-1N. The relatively short half-live may limit in vivo use. Not recommended for oral use due to lack of data.