WDR5-IN-5

• CAT Number: I043324
• CAS Number: 2417012-26-9
• Molecular Formula: C29H29F3N6O
• Molecular Weight: 534.58
• Purity: ≥95%
• Synonyms: 2-[(S)-cyclopropyl-(4-methylpyridin-2-yl)methyl]-5-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-7-(imidazol-1-ylmethyl)-3,4-dihydroisoquinolin-1-one
• InChI: InChI=1S/C29H29F3N6O/c1-3-37-16-24(27(35-37)29(30,31)32)22-13-19(15-36-11-9-33-17-36)14-23-21(22)7-10-38(28(23)39)26(20-4-5-20)25-12-18(2)6-8-34-25/h6,8-9,11-14,16-17,20,26H,3-5,7,10,15H2,1-2H3/t26-/m0/s1
• InChIKey: FFUQRXFVTVBZMZ-SANMLTNESA-N
• SMILES: CCN1C=C(C(=N1)C(F)(F)F)C2=C3CCN(C(=O)C3=CC(=C2)CN4C=CN=C4)C(C5CC5)C6=NC=CC(=C6)C

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[1].
WDR5 plays an important role in the activity of MLL1 histone methyltransferase (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 (ethylene 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]

Route
Dose (mg/kg)
CL (mL/min/kg)
AUC0,inf (h.ng/mL)
Vss (L/kg)
T1/2 (h)
F (%)

i.v.
3
26
1951
1.6
/
/

p.o.
10
2083
3984
/
1.3
61

Reference

[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.
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