DRI-C21045
目录号 : GC39312DRI-C21045 (compound 10) 是一种有效和选择性的 CD40-CD40L 共刺激蛋白-蛋白质相互作用 (PPI) 抑制剂,IC50 为 0.17 μM。DRI-C21045 显示对 CD40L 诱导的 NF-κB 活化和 B 细胞增殖的浓度依赖性抑制,IC50 分别为 17.1 μM 和 4.5 μM。
Cas No.:2101765-81-3
Sample solution is provided at 25 µL, 10mM.
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DRI-C21045 (compound 10) is a potent and selective inhibitor of the CD40-CD40L costimulatory protein-protein interaction (PPI) with an IC50 of 0.17 µM. DRI-C21045 shows concentration-dependent inhibition of the activation of NF-κB and B cell proliferation all induced by CD40L with IC50s of 17.1 µM and 4.5 µM, respectively[1].
[1]. Chen J, et al. Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction. J Med Chem. 2017 Nov 9;60(21):8906-8922.
Cas No. | 2101765-81-3 | SDF | |
Canonical SMILES | O=S(C1=CC=CC2=CC=CC(NC(C3=CC=C(C4=CC=C(NC(C5=CC=C(C(OC)=O)C=C5)=O)C=C4)C=C3)=O)=C21)(C)=O | ||
分子式 | C33H26N2O6S | 分子量 | 578.63 |
溶解度 | DMSO: 2 mg/mL (3.44 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.7282 mL | 8.6411 mL | 17.2822 mL |
5 mM | 0.3456 mL | 1.7282 mL | 3.4564 mL |
10 mM | 0.1728 mL | 0.8641 mL | 1.7282 mL |
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2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction
J Med Chem 2017 Nov 9;60(21):8906-8922.PMID:29024591DOI:10.1021/acs.jmedchem.7b01154.
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.
Toward Small-Molecule Inhibition of Protein-Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions
Curr Top Med Chem 2018;18(8):674-699.PMID:29848279DOI:10.2174/1568026618666180531092503.
Protein-Protein Interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable. Nevertheless, substantial progress has been achieved during the last decade. SMPPIIs proving the feasibility of such approaches have been identified through various strategies for a number of cosignaling interactions including CD40-CD40L, OX40-OX40L, BAFFR-BAFF, CD80-CD28, and PD-1-PD-L1s. Here, after an overview of the general aspects and challenges of SMPPII-focused drug discovery, we review them briefly together with relevant structural, immune-signaling, physicochemical, and medicinal chemistry aspects. While so far only a few of these SMPPIIs have shown activity in animal models (DRI-C21045 for CD40-D40L, KR33426 for BAFFR-BAFF) or reached clinical development (RhuDex for CD80-CD28, CA-170 for PD-1-PD-L1), there is proof-of-principle evidence for the feasibility of such approaches in immunomodulation. They can result in products that are easier to develop/ manufacture and are less likely to be immunogenic or encounter postmarket safety events than corresponding biologics, and, contrary to them, can even become orally bioavailable.