E-7046

• CAT Number: I011760
• CAS Number: 1369489-71-3
• Molecular Formula: C₂₂H₁₈F₅N₃O₄
• Molecular Weight: 483.41
• Purity: ≥95%
• Synonyms: 4-[(1S)-1-[[[3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-1H-pyrazol-4-yl]carbonyl]amino]ethyl]-benzoic acid
• Target: Prostaglandin Receptor
• Solubility: Soluble in DMSO
• Storage: Store at -20°C
• IUPAC Name: 4-[(1S)-1-[[3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]pyrazole-4-carbonyl]amino]ethyl]benzoic acid
• InChI: InChI=1S/C22H18F5N3O4/c1-11(12-6-8-13(9-7-12)21(32)33)28-19(31)16-17(18(23)24)29-30(2)20(16)34-15-5-3-4-14(10-15)22(25,26)27/h3-11,18H,1-2H3,(H,28,31)(H,32,33)/t11-/m0/s1
• InChIKey: MKLKAQMPKHNQPR-NSHDSACASA-N
• SMILES: C[C@@H](C1=CC=C(C=C1)C(=O)O)NC(=O)C2=C(N(N=C2C(F)F)C)OC3=CC=CC(=C3)C(F)(F)F

E-7046 (Cat No.:I011760) is a selective antagonist of the prostaglandin E2 (PGE2) receptor EP4 subtype. It functions by blocking the binding of PGE2 to the EP4 receptor, thereby inhibiting the downstream signaling pathways activated by EP4 receptor activation. By antagonizing EP4, E-7046 has demonstrated anti-inflammatory effects and has shown potential therapeutic applications in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. Additionally, E-7046 has also been investigated for its potential anti-tumor activity, as EP4 signaling is implicated in promoting tumor growth and progression.

Reference

1. Oncoimmunology. 2017 Jun 28;6(8):e1338239. doi: 10.1080/2162402X.2017.1338239.
eCollection 2017.

EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with
Treg-reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor
immunity.

Albu DI(1), Wang Z(1), Huang KC(1), Wu J(1), Twine N(1), Leacu S(1), Ingersoll
C(1), Parent L(1), Lee W(1), Liu D(1), Wright-Michaud R(1), Kumar N(1), Kuznetsov
G(1), Chen Q(1), Zheng W(1), Nomoto K(2), Woodall-Jappe M(2), Bao X(1).

Author information:
(1)Andover Innovative Medicines Institute, Eisai Inc., Andover, MA, USA.
(2)Oncology Business Group, Eisai Inc., Woodcliff Lake, NJ, USA.

Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting
alternatively activated tumor associated macrophages (M2TAM), myeloid-derived
suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising
strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an
arachidonic acid pathway metabolite and mediator of chronic inflammation, has
emerged as a powerful immunosuppressor in the TME through engagement with one or
more of its 4 receptors (EP1-EP4). We have developed E7046, an orally
bioavailable EP4-specific antagonist and show here that E7046 has specific and
potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell
differentiation and activation. E7046 treatment reduced the growth or even
rejected established tumors in vivo in a manner dependent on both myeloid and
CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an
IL-2-diphtheria toxin fusion protein that preferentially kills Tregs,
synergistically disrupted the myeloid and Treg immunosuppressive networks,
resulting in effective and durable anti-tumor immune responses in mouse tumor
models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+
cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic
inflammation phenotype into acute inflammation, shown by substantial induction of
STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic
anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been
reported to diminish intratumoral Tregs. Our studies thus reveal a specific
myeloid cell differentiation-modifying activity by EP4 blockade and a novel
combination of E7046 and E7777 as a means to synergistically mitigate both
myeloid and Treg-derived immunosuppression for cancer treatment in preclinical
models.