PF-06928215 cis-racemate contains the (1R,2S) and (1S,2R) cis-enantiomers of a small-molecule cyclic GMP-AMP synthase (cGAS) inhibitor. Its formula is C20H20N4O4 and its molecular weight is 380.40 g/mol.
Application of PF-06928215 cis-racemate
The PF-06928215 cGAS inhibitor series has been studied using surface plasmon resonance to measure binding, biochemical assays to quantify cGAMP production, and X-ray crystallography to characterize binding in the cGAS active site.
For work with the racemate, establish a concentration-response curve under the intended assay conditions and report concentrations on a total-racemate basis. Intact-cell interferon assays require separate confirmation of cellular target engagement.
In Vitro
Published measurements for the (1R,2S) enantiomer of PF-06928215 include a Kd of 200 nM and an enzymatic IC50 of 4.9 µM. The latter was measured with 1 mM ATP, 0.3 mM GTP and 100 nM 45-bp interferon-stimulatory dsDNA. Substrate competition contributes to the difference between nucleotide-free binding measurements and functional assays.
The discovery study found no inhibition of dsDNA-induced IFN-β reporter expression, with minimal effects on viability. Limited permeability and competition from intracellular nucleotides were proposed explanations, rather than established causes.
In Vivo
The original report on the cGAS inhibitor PF-06928215 did not establish animal efficacy, pharmacokinetics or an in vivo dosing regimen. Its biochemical results therefore provide no basis for selecting an effective animal dose. The negative cellular result also leaves target engagement in tissues unresolved; it does not prove that animal activity is impossible.
Biochemical and Physiological Actions
DNA-activated cGAS converts ATP and GTP into 2′3′-cGAMP, which activates STING and downstream interferon signaling. The inhibitor series binds in the nucleotide-binding active site, reducing cGAMP synthesis rather than directly blocking STING.
The PF-06928215 cis-racemate structure retains the cis relationship between the neighboring carboxylic acid and carboxamido substituents on the cyclohexane ring. Its two components have opposite absolute configurations. Their relative contributions to inhibition require measurement; a fixed twofold loss of potency cannot be assumed from racemic composition alone.
Features and Benefits of PF-06928215 cis-racemate
CAS 2570808-90-9 identifies the cis-racemate for sourcing and documentation checks. Confirm the stereochemical designation as well as molecular identity: chemical purity alone does not establish enantiomeric composition or functional potency.
The combination of a defined scaffold and published binding and enzyme-assay methods supports comparative biochemical studies. Record the enzyme construct, nucleotide concentrations and stereochemical form when comparing results, and use batch documentation for preparation and storage conditions.
Powered by Bioz