WDR5-IN-5 is an orally active and selective inhibitor of WIN site of WD repeat domain 5 (WDR5). WDR5-IN-5 exhibits anti-proliferative activity towards cancer cells and good pharmacokinetics profile in mice. WDR5-IN-5 shows high affinity to WDR5 and the binding affinity Ki value <0.02 nM.
WDR5 plays an important role in the activity of MLL1 histone metltransferase (HMT) complexes. WDR5-IN-5 (compound 41), as a WDR5 inhibitor, will exihibits inhibitory effect towards HMT[1].WDR5-IN-5 displays average soluble concentrations (kinetic solubility) of 60 μM[1].WDR5-IN-5 exhibits high selectivity between K562 cells and MV4:11, the selectivity index (GI50, K562/GI50, MV4:11) is 290[1].WDR5-IN-5 (0-30 μM; 5 d) inhibits cell proliferation of MV4:11, MOLM-13, and K562 with GI50 values are 13, 27, 3700 nM, respectively[1].
WDR5-IN-5 (compound 41) (10 mg/kg; p.o.) shows high oral exposure (AUC0,inf=3984 h.ng/mL), long half-life of T1/2=1.3 h[1].WDR5-IN-5 (3 mg/kg; i.v.) also shows low iv clearance (26 mL/min/kg). WDR5-IN-5 is well tolerated and shows no adverse effects in mice by both i.v. and p.o. dosing[1].WDR5-IN-5 can be formulated as 0.6 and 1 mg/mL solutions in ethanol, tocopherol poly (etlene glycol) succinate (TPGS), PEG400 and water (v/v/v/v, 5/5/30/60) for i.v. and p.o. dosing, respectively[1].PK profile of WDR5-IN-5 in CD-1 Mice[1]
References:
[1]. Teuscher KB, et al. Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization. J Med Chem. 2022 Apr 28. 65(8):6287-6312.