- Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction
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Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1-TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein-protein interactions, establish the structural requirements needed for efficient CD40-CD40L inhibition, and serve to guide the search for such immune therapeutics.
- Chen, Jinshui,Song, Yun,Bojadzic, Damir,Tamayo-Garcia, Alejandro,Landin, Ana Marie,Blomberg, Bonnie B.,Buchwald, Peter
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supporting information
p. 8906 - 8922
(2017/11/14)
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- Functionalization of fatty acid mimetics for solid-phase coupling and subsequent target identification
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Fatty acid mimetics such as pirinixic acid (PA) derivatives and 2-(phenylthio)alkanoic acid derivatives are drug-like small molecules with an interesting pharmacological profile. Previously, we have characterized PA derivatives (e.g., 1) as dual agonists
- Dittrich, Michaela,Zettl, Heiko,Schubert-Zsilavecz, Manfred
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experimental part
p. 625 - 630
(2011/09/14)
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- PIPERAZINE AND HOMOPIPERAZINE COMPOUNDS
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Compounds are provided having a piperazine or homopiperazine ring which are useful in the treatment of thrombosis.
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- Derivatives of aminobenzoic and aminobiphenylcarboxylic acids useful as anti-cancer agents
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The present invention provides compounds having the formula: wherein n is0or1; R is —NH2or wherein R1and R2are independently selected from the group consisting of H, alkyl, aralkyl, heteroaralkyl, carboxy, carboxyalkyl, and carbamoyl; Q is R3C(O)— or wherein R5is selected from the group consisting of H, alkyl, aralkyl, heteroaralkyl, and carbamoylalkyl, and R3and R4are selected from the group consisting of H, alkyl, alkoxy, arylalkoxy, aralkyl, heteroaralkyl, and carbamoylalkyl; the Q—NH—(CH2)n— and the —C(O)R substituents of the compound of formula I are independently positioned ortho, meta, orpara relative to the carbon atoms that form the bond between the two phenyl groups to which said substituents are bound, with the proviso that said substituents are not both positioned ortho; and the Q—NH—(CH2)nand the —C(O)R substituents of the compound of formula II are positioned meta orpara to each other; or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof. The compounds are useful for treating uPA- or uPAR-mediated disorders, e.g., tumor metastasis, tumor angiogenesis, restenosis, chronic inflammation, or corneal angiogenesis.
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- Construction of a family of biphenyl combinatorial libraries: Structure- activity studies utilizing libraries of mixtures
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A set of biphenyl aminoacid building blocks has been synthesized. These were used to construct partially-peptidic combinatorial libraries as equimolar multi-component samples. Activity of members of this library as vitronectin receptor antagonists is described, together with SAR studies of the most active members. These studies illustrate several important features of combinatorial libraries.
- Neustadt, Bernard R.,Smith, Elizabeth M.,Lindo, Neil,Nechuta, Terry,Bronnenkant, Alan,Wu, Arthur,Armstrong, Lydia,Kumar, Chandra
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p. 2395 - 2398
(2007/10/03)
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- NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein
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The E2 protein is required for the replication of human papillomaviruses (HPVs), which are responsible for anogenital warts and cervical carcinomas. Using an NMR-based screen we tested compounds for binding to the DNA-binding domain of the HPV-E2 protein. Three classes of compounds were identified which bound to two distinct sites on the protein. Biphenyl and biphenyl ether compounds containing a carboxylic acid bind to a site near the DNA recognition helix and inhibit the binding of E2 to DNA. Benzophenone- containing compounds which lack a carboxylic acid group bind to the β- barrel formed by the dimer interface and exhibit negligible effects on the binding of E2 to DNA. Structure-activity relationships from the biphenyl and biphenyl ether compounds were combined to produce a compound [5-(3'- (3'',5''-dichlorophenoxy)-phenyl)-2,4-pentadienoic acid] with an IC50 value of approximately 10 μM. This compound represents a useful lead for the development of antiviral agents that interfere with HPV replication and further illustrates the usefulness of the SAR by NMR method in the drug discovery process.
- Hajduk, Philip J.,Dinges, Jürgen,Miknis, Gregory F.,Merlock, Megan,Middleton, Tim,Kempf, Dale J.,Egan, David A.,Walter, Karl A.,Robins, Terry S.,Shuker, Suzy B.,Holzman, Thomas F.,Fesik, Stephen W.
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p. 3144 - 3150
(2007/10/03)
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- 2-(BIPHENYL-4-YL)-5-PHENYL-1,3,4-OXADIAZOLE (PBD): ELECTROPHILIC 4'-SUBSTITUTION AND FOLLOWING TRANSFORMATIONS
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PBD was converted into 4'-substituted derivatives I-XII using usual electrophilic reagents.The decompositions of PBD, 4'-acetyl derivative I and 4'-nitro derivative VI with hydroiodic acid gave 4'-substituted 4-biphenylcarboxylic acids XIIIa-XIIIc and benzoic acid, respectively.The regioselectivity of the reactions was also proved by means of high resolution NMR spectroscopy.
- Kurfuerst, Antonin,Lhotak, Pavel,Nadenik, Petr,Raclova-Pavlikova, Frantiska,Kuthan, Josef
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p. 1495 - 1504
(2007/10/02)
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