LUF7996 

LUF7996 is a CCR2 PROTAC Degrader degrading CCR2 with DC₅₀ = 2.6 μM. LUF7996 demonstrates engagement of both and the E3 ligase cereblon and displays sustain and concentration-dependent degradation of CCR2. LUF7996 reliance on the lysosomal pathway to induce CCR2 degradation. LUF7996 efficiently inhibits monocyte migration in virto^[1]. (Pink: CCR2 ligand (HY-180572); Blue: Cereblon ligand (HY-41547); Black: linker).

LUF7996 (compound 10) (10 μM) displaces [³H]CCR2-RA-[R] with pKi = 6.9 nM and displays < 50 % inhibiton in U2OS-CCR2 cells^[1].
LUF7996 (0.1-31.6 μM, 2 h) not display any substantial degradative capacity when tested at concentrations below 1 μM, has a rapid and concentration-dependent degradation of CCR2 with DC₅₀= 5.6 μM without indication of a hook effect at concentrations higher than 1 μM, D_max = 85% at 31.6 μM and D_max = 79% at 10 μM in HEK293-LgBiT cells^[1].
LUF7996 binds CCR2 with IC₅₀ = 7.858 μM, exhibits the strongest CRBN engagement with IC₅₀ = 143 μM^[1].
LUF7996 (10 μM, 12 or 24 h) mediated CCR2 degradation is rescued upon cotreatment with either a CRBN inhibitor (competing for the binding pocket) or a CRBN degrader^[1].
LUF7996 (10 μM, 3 h) result a significant increase in CCR2 ubiquitination, degrades CCR2 least partially through CRBN and ubiquitin-dependent mechanisms^[1].
LUF7996 (10 μM, 0-25 h) did not block CCR2 degradation but enhances CCR2 degradation after 16h when cotreat with proteasome inhibitors Bortezomib (HY-10227) or MG-132 (HY-13259) (10 μM) or the neddylation inhibitor MLN-4924 (HY-70062) (250 nM), suggesting a proteasome-and neddylation-independent mechanism of action^[1].
LUF7996 (10 μM, 0-25 h) has CCR2 degradative effect but prevented by inhibition of the lysosomal pathway, as evidenced by the full restoration of CCR2 levels with Baf-A1 (HY-100558) and the decreased degradation observed with Chloroquine (HY-17589A)^[1].
LUF7996 (10 μM, 24 h) results a significant reduction in [ 3 H]CCR2-RA- [R] binding in THP-1 cells, indicating a reduction of CCR2 levels^[1].
LUF7996 (10 μM) demonstrates 84% potent inhibition of CCL2-induced monocyte migration in THP-1 cells^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

860.68

C₃₉H₃₄Cl₂F₃N₅O₈S

3104736-80-0

ClC1=CC=C(OC2=CC=C(C(NCCCCCCNC3=CC=CC(C(N4C5CCC(NC5=O)=O)=O)=C3C4=O)=O)C=C2)C(NS(C6=CC=C(Cl)C(C(F)(F)F)=C6)(=O)=O)=C1

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• [1]. Essa K, et al. Leveraging Targeted Protein Degradation for G Protein-Coupled Receptors: The Development of CCR2 Molecular Degraders. J Med Chem. 2025 Dec 25;68(24):26525-26546.  [Content Brief]