cAIM(PS)2 Difluor (Rp/Sp) (CL656)

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cAIM(PS)2 Difluor (Rp/Sp)

cAIMP bisphosphorothioate and difluorinated, a STING ligand

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5 x 100 µg

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cAIMP bisphosphorothioate and difluorinated

InvivoGen's cAIM(PS)2 Difluor (Rp/Sp) (also known as CL656) is a synthetic cyclic dinucleotide (CDN) and potent agonist of the endoplasmic reticulum-resident receptor STING (stimulator of interferon genes) [1-3]. It is composed of Rp/Sp-isomers of the bisphosphorothioate derivative of cAIMP, an analog of the bacterial cyclic dinucleotide (CDN) 3'3'-cGAMP [1-2]. The binding of cAIM(PS)2 Difluor (Rp/Sp) to STING triggers the expression of interferon-β (IFN-β) and nuclear factor-κB (NF-κB) dependent inflammatory cytokines [1]. 
STING has been a privileged target for developing immunomodulatory therapeutics [3, 4]. Of note, cAIM(PS)2 Difluor (Rp/Sp) has entered clinical trials for treating advanced/metastatic, recurrent, solid tumors, with emphasis on squamous cell carcinoma of the head and neck, triple-negative breast cancer, anaplastic thyroid carcinoma, and cutaneous squamous cell carcinoma [5]. CL656 can be considered a clinically relevant safe STING agonist since it has been successfully administered in humans in combination with exosomes (ExoSTING) [3,5].  

Key Features

  • Unlike natural CDNs, whose constituent nucleosides are guanosine and/or adenine, cAIMP and its derivatives contain one adenine nucleoside and one inosine nucleoside. cAIM(PS)2 Difluor (Rp/Sp) is composed of two 2’-deoxynucleosides with a fluorine atom at the 2’ position of each nucleoside for improved stability [5]. 
  • A clinically relevant safe STING agonist successfully administered in humans to treat advanced solid tumors [3,5].
  • In addition, this cAIMP analog contains two phosphorothioate diester linkages, which prevent its degradation by the phosphodiesterases that are present in host cells or in the systemic circulation [6].
  • 2’3’‑cGAMP, cAIM(PS)2 Difluor (Rp/Sp) (referred to as compound 53 by Lioux et al. [1]) is more potent than 2’3’‑cGAMP for STING activation [1].


CL-656 was licensed by Kayla Therapeutics to Codiak Biosciences for therapeutic purposes.

Note: InvivoGen has developed stable STING reporter cells in two well-established immune cell models: THP-1 human monocytes and RAW 264.7 murine macrophages. These cells express inducible SEAP and/or Lucia luciferase reporter genes under the control of an IRF-inducible or NF-κB-inducible promoter.




1. Lioux T. et al., 2016. Design, synthesis, and biological evaluation of novel cyclic adenosineinosine monophosphate (cAIMP) analogs that activate stimulator of interferon genes (STING). J Med Chem. 59:10253-10267.
2. Cyclic dinucleotides for cytokine induction, patent US10011630B2 and foreign equivalents.
3. Jang S., et al. 2021. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun. Biol. 4:497.
4. Zhang H., et al. 2020. Targeting Stimulator of Interferon Genes (STING): a medicinal chemistry perspective. Journal of Medicinal Chemistry. 63(8):3785.
6. Böhm H.J. et al., 2004. Fluorine in medicinal chemistry. Chembiochem. 5:637-43.
7. Yan H. et al., 2008. Synthesis and immunostimulatory properties of the phosphorothioate analogs of cdiGMP. Bioorg. Med. Chem. Lett. 18, 5631–5634.


IRF INDUCTION (Lucia luciferase reporter)
IRF INDUCTION (Lucia luciferase reporter)

THP1-Dual™ cells were stimulated for 24 hours with human IFN-β (1 x 104 U/ml), TNF-α (300 pg/ml), cAIMP, cAIMP Difluor, cAIM(PS)2 Difluor (Rp/Sp), 2’3’-cGAMP and 2’3’-cGAM(PS)2 (Rp/Sp). All CDNs were used at 10 μg/ml.
IRF induction was determined by measuring the relative light units (RLUs) in a luminometer using QUANTI‑Luc™, a Lucia luciferase detection reagent. The IRF induction of each ligand is expressed relative to that of hIFN-β at 1 x 104 U/ml (taken as 100%).


THP1-Dual™ cells were stimulated for 24 hours with human IFN-β (1x104U/ml), TNF-α (300pg/ml), cAIMP, cAIMP Difluor, cAIM(PS)2 Difluor (Rp/Sp), 2’3’-cGAMP and 2’3’-cGAM(PS)2 (Rp/Sp). All CDNs were used at 10μg/ml.
NF-κB induction was determined using QUANTI‑Blue™, a SEAP detection reagent, and by reading the optical density (OD) at 655 nm. TNF-α has been included as a positive control to activate the NF-κB signaling pathway.

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Source: Synthetic

Synonym: (Rp/Sp) c-[2’FdAM(PS)-2’FdIM(PS]) sodium salt

CAS: 1951464-79-1

Formula: C20H21F2N9O9P2S2 .2Na

Molecular weight: 695.5 (free acid), 739.5 (sodium salt)

Solubility: 50 mg/ml in water

Quality control:

  • Purity and structure has been determined by LC/MS and NMR: ≥ 95%
  • The biological activity has been confirmed using cellular assays.
  • The absence of bacterial contamination (e.g. lipoproteins & endotoxins) has been confirmed using HEK-Blue™ TLR4 and HEK-Blue™ TLR2 cells.
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  • 5 x 100 µg of cAIM(PS)2 Difluor (Rp/Sp) provided lyophilized.
    Note: This product is sterile filtered prior to lyophilization.
    cAIM(PS)2 Difluor (Rp/Sp) is a mixture of Rp/Sp diastereoisomers.
  • 1.5 ml endotoxin-free water
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cAIM(PS)2 Difluor (Rp/Sp) chemical structure

cAIM(PS)2 Difluor (Rp/Sp) chemical structure

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