BellBrook’s lead discovery services specialize in small molecule modulators for enzyme drug candidates. Our experts work diligently with varieties of customers in early-stage drug discovery programs to identify actives from a virtual screen, prioritize high throughput screening (HTS) hits, or generate quantitative data to drive SAR/medicinal chemistry efforts.
BellBrook scientists performed an inhibitor screening & inhibitor potency profiling of cGAS using the Transcreener cGAMP cGAS Assay.
Screen of 1600 compounds. cGAS was used at 10 nM, compounds were at 10 μM. Z=0.62, Z’=0.7 illustrate a robust screening assay. Hits were determined to be anything outside three standard deviations from the mean.
Confirmation of a screening hit using the Transcreener cGAMP cGAS Assay in the FP format. Follow-up assays to triage screening hits can be used to selective bonafide inhibitors for advancement into medicinal chemistry/SAR.
Determination of koff using ‘jump dilution’ enzymatic assay method. Inhibitors are preincubated with enzyme at saturating concentration to allow formation of E-I complexes, then diluted 100-fold into the reaction mix. Recovery of enzyme activity correlates with inhibitor dissociation. Activity recovers as the E-I complex dissociates, allowing calculation of off-rates.
Screen of 1600 compounds. cGAS was used at 10 nM, compounds at 10 μM. Z = 0.62, Z’ = 0.7 illustrate a robust screening assay. Hits were determined to be anything outside of three standard deviations from the mean.
Confirmation of a screening hit using the Transcreener cGAMP cGAS Assay in the FP format. Follow-up assays to triage screening hits can be used to selective bonafide inhibitors for advancement into medicinal chemistry/SAR.
During drug development initiatives, analysis of drug-target residence times can improve efficacy, increase therapeutic window, and reduce the risk of premature focus on candidate compounds that are likely to have undesirable side effects.
Identification of non-stoichiometric inhibitors (NSI) using inhibitor titration and detergent disaggregation. Non-ionic detergent can dispense aggregates, resulting in decreased IC50 (above). Excess enzyme titrates out NSIs resulting in a significant increase in IC50 (not shown).
Weed-out non-stoichiometric inhibitors by performing assays under different conditions such as varying detergent and enzyme concentration. Reduce wasted time on compounds you can’t move forward by eliminating them earlier.
BellBrook scientists will perform thermal shift assays for your target protein and compound to determine a change in protein melting temperature. Shifts in protein melting temperature upon addition of a compound indicate compound-target interaction. Here, we see a shift in the melting temperature of cGAS with 2 inhibitors, an internally discovered compound 993, and known cGAS inhibitor, PF-06928215. Learn more about our Thermal Shift Assay services here.
BellBrook’s Transcreener® HTS assay platform is ideally suited for the detailed biochemical and kinetic analyses required for hit-to-lead programs. Transcreener® is an extensively validated HTS platform that produces robust FP, TR-FRET, and FI signals for nucleotides produced by enzymes; e.g. ADP for kinases. It has been used to screen tens of millions of wells over the last 10 years in pharma and biotech labs.
Because they use direct immunodetection of nucleotides, Transcreener® assays can provide more reliable results than alternative methods that rely on complicated schemes involving coupling enzymes. In addition, the ability to run Transcreener® assays in continuous mode enables analysis of inhibitor binding kinetics such as residence time, which is increasingly recognized as an important factor for drug efficacy. For our services, additional assay methods will be employed as needed to meet customer requirements.
Leveraging BellBrook’s services expertise will save you time and money. Your project will be handled by the same BellBrook scientists who developed the Transcreener assay and have optimized them for more than 100 different enzymes, including kinases, ATPases, GTPases, glycosyltransferases, ligases/synthetases, and phosphodiesterases. We will tailor our efforts to meet your specific needs. For example, minimizing consumption of limited reagents or enabling simultaneous screening for inhibitors and activators. And we will work fast. If your target enzyme is in good shape, we can generally complete the services within two to four weeks.
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What do your Lead Discovery Services include?
BellBrook Labs supports early-stage drug discovery by offering:
Inhibitor Screening: Identify or confirm active compounds against your target.
Inhibitor Potency Profiling: Quickly derive IC₅₀ values using dose-response assays with target or related proteins.
Inhibitor Selectivity Profiling: Compare compound activity across multiple proteins to guide specificity assessments.
Residence Time Measurements: Use ‘jump’ dilution enzymatic assays to estimate koff and binding duration.
Mechanism of Action Studies: Determine how inhibitors act through detailed kinetic analyses.
Triaging Non-Stoichiometric Inhibitors: Use variations in detergent or enzyme concentrations to flag problematic compounds.
Compound–Target Binding Assessment: Employ thermal shift assays to confirm binding by measuring changes in melting temperature.
How do Lead Discovery Services fit into the drug discovery process?
BellBrook Labs leverages expertise in enzymology and its Transcreener platform to accelerate hit identification, profiling, and prioritization—all vital for SAR (Structure–Activity Relationship) and lead optimization.
What technologies underpin your Lead Discovery offerings?
Our assays utilize the Transcreener HTS platform, providing robust detection via fluorescence polarization (FP), fluorescence intensity (FI), or TR-FRET—directly targeting enzyme products like nucleotides. This enables both kinetic and endpoint assays with minimal interference.
Can I see an example of your services in action?
Yes. BellBrook’s scientists applied inhibitor screening and potency profiling to human cGAS using the Transcreener cGAMP assay:
Screened 100,000 compounds at 10 μM concentration, with 10 nM cGAS.
Achieved robust assay statistics ( Z′ = 0.7).
Hits were identified as values outside three standard deviations from the mean.
What types of targets are suitable for your Lead Discovery services?
Services are tailored for small-molecule modulators of enzyme targets, including kinases, methyltransferases, ATPases, GTPases, phosphodiesterases, ligases, synthetases, helicases, and emerging targets such as cGAS—leveraging our Transcreener assays.
How quickly can these services be delivered?
BellBrook typically completes assay-related projects (such as initial screening or profiling) in a timely manner, especially when the target enzyme is well-suited—supported by streamlined workflows and years of experience. 1-2 weeks is standard, and can be down to days when aligned with customer needs.
Why choose BellBrook Labs over other CROs?
Specialized enzymology proficiency ensures in-depth understanding of kinetics and assay development.
Robust assay performance: Transcreener assays deliver reliable and reproducible results validated over millions of wells.
Comprehensive service scope: From hit identification to kinetic profiling, all stages of lead discovery are covered.
BellBrook Labs
1232 Fourier Drive, Suite 115
Madison, Wisconsin 53717 USA
(608) 443-2400
info@bellbrooklabs.com
