Donated Chemical Probes

Target	PDE10A
Targeted domain	Hydrophobic clamp of the catalytic site
Mode of action	Inhibitor
Control	JNJ-40573663
Orthogonal probe	THPP-1
Recommended cellular usage concentration	≤ 10 µM
In vivo use	Yes
Donated by	Johnson & Johnson

Inhibitor/agonist potency: goal is < 100 nM (IC₅₀, K_d)	Surpasses criterion: human PDE10A ([3H]cAMP substrate) K_i = 13 nM (SPA); rat PDE10A: K_i = 19 nM; mouse PDE10A: K_i = 11 nM Inhibition of cAMP and cGMP hydrolysis by isolated hPDE10A enzyme: cAMP IC₅₀ = 40 nM, cGMP IC₅₀ = 51 nM
Selectivity within target family: > 30-fold	Surpasses criterion: PDE selectivity > 250 fold: closest hit is PDE1B with K_i = 3.4 µM (257 fold)
Selectivity outside target family	CEREP receptor and enzyme panel (50) at 10 µM: clean Millipore kinase panel (203) at 10 µM: all inhibition < 50 % Closest off-targets in the PDSP scan are HTR2C Ki =2197.87 nM, HTR2B Ki =2293.19 nM and HTR7 Ki = 8744.82 nM.
On target cell activity for cell-based targets: goal is < 1 µM IC₅₀/EC₅₀	Concentration-dependent increase in luciferase activity in PDE10A CRE-Luc transfected HEK293 cells: 2.3 fold increase at 1 μM; 10 fold increase at 10 μM; In wild type HEK293 cells no increase in luciferase activity was measured at these concentrations.
Control compound (100 times less potent than the probe)	Surpasses criterion: JNJ-40573663: human PDE10A IC₅₀ > 10 µM (in vitro assay) Closest off-targets in the GPCR scan are GABAA (Ki =1822.22 nM) and SLC6A3 (Ki =4132.38 nM).