Diprovocim-1
目录号 : GC48352An agonist of TLR1/TLR2
Cas No.:2170867-89-5
Sample solution is provided at 25 µL, 10mM.
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Diprovocim-1 is an agonist of the toll-like receptor 1/2 heterodimer.1 It induces TNF-α release in THP-1 cells (EC50 = 110 pM), an effect that can be inhibited by anti-TLR1 or anti-TLR2 antibodies. Diprovocim-1 (10 mg/kg) increases the production of ovalbumin-specific IgG1 in wild-type, but not TLR2-/-, mice sensitized to ovalbumin.2 It also enhances anti-PD-L1 antibody-induced activation of cytotoxic T lymphocytes, reduction of tumor growth, and increases in survival in a B16/F10 murine melanoma model.
1.Morin, M.D., Wang, Y., Jones, B.T., et al.Diprovocims: A new and exceptionally potent class of toll-like receptor agonistsJ. Am. Chem. Soc.140(43)14440-14454(2018) 2.Wang, Y., Su, L., Morin, M.D., et al.Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in miceProc. Natl. Acad. Sci. U.S.A.115(37)E8698-E8706(2018)
Cas No. | 2170867-89-5 | SDF | |
Canonical SMILES | O=C(C1=CC=C(C=C1)C(N2C[C@@H](C(N[C@@H]3[C@](C4=CC=CC=C4)([H])C3)=O)[C@H](C(N[C@@H]5[C@](C6=CC=CC=C6)([H])C5)=O)C2)=O)N7C[C@@H](C(N[C@@H]8[C@](C9=CC=CC=C9)([H])C8)=O)[C@H](C(N[C@@H]%10[C@](C%11=CC=CC=C%11)([H])C%10)=O)C7 | ||
分子式 | C56H56N6O6 | 分子量 | 909.1 |
溶解度 | DMSO: soluble | 储存条件 | -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.1 mL | 5.4999 mL | 10.9999 mL |
5 mM | 0.22 mL | 1.1 mL | 2.2 mL |
10 mM | 0.11 mL | 0.55 mL | 1.1 mL |
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2.
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Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists
J Am Chem Soc 2018 Oct 31;140(43):14440-14454.PMID:30272974DOI:10.1021/jacs.8b09223.
A screen conducted with nearly 100000 compounds and a surrogate functional assay for stimulation of an immune response that measured the release of TNF-α from treated human THP-1 myeloid cells differentiated along the macrophage line led to the discovery of the diprovocims. Unique to these efforts and of special interest, the screening leads for this new class of activators of an immune response came from a compound library designed to promote cell-surface receptor dimerization. Subsequent comprehensive structure-activity relationship studies improved the potency 800-fold over that of the screening leads, providing Diprovocim-1 and diprovocim-2. The diprovocims act by inducing cell-surface toll-like receptor (TLR)-2 dimerization and activation with TLR1 (TLR1/TLR2 agonist), bear no structural similarity to any known natural or synthetic TLR agonist, and are easy to prepare and synthetically modify, and selected members are active in both human and murine systems. The most potent diprovocim (3, Diprovocim-1) elicits full agonist activity at extraordinarily low concentrations (EC50 = 110 pM) in human THP-1 cells, being more potent than the naturally derived TLR1/TLR2 agonist Pam3CSK4 or any other known small molecule TLR agonist.
Next-Generation Diprovocims with Potent Human and Murine TLR1/TLR2 Agonist Activity That Activate the Innate and Adaptive Immune Response
J Med Chem 2022 Jul 14;65(13):9230-9252.PMID:PMC9283309DOI:10.1021/acs.jmedchem.2c00419.
The diprovocims, a new class of toll-like receptor (TLR) agonists, bear no similarity to prior TLR agonists, act through a well-defined mechanism (TLR1/TLR2 agonist), exhibit exquisite structure-activity relationships, and display in vivo adjuvant activity. They possess potent and efficacious agonist activity toward human TLR1/TLR2 but modest agonism toward the murine receptor. A manner by which diprovocims can be functionalized without impacting hTLR1/TLR2 activity is detailed, permitting future linkage to antigenic, targeting, or delivery moieties. Improvements in both potency and its low efficacy in the murine system were also achieved, permitting more effective use in animal models while maintaining the hTLR1/TLR2 activity. The prototypical member diprovocim-X exhibits the excellent potency/efficacy of Diprovocim-1 in human cells, displays substantially improved potency/efficacy in mouse macrophages, and serves as an adjuvant in mice when coadministered with a nonimmunogenic antigen, indicating stimulation of the adaptive as well as innate immune response.