Lead Discovery Services

Learn More About BellBrook's Drug Discovery Services

Lead Discovery Services Offered By BellBrook Labs

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. 

Lead Discovery Services Graphic

Lead Discovery Services

Scientists Performing Lead Drug Discovery Services
  • Inhibitor Screening - To identify or confirm activity with the target.
  • Inhibitor Potency Profiling - Dose-response with target and/or related proteins. Fast IC50 results.
  • Inhibitor Selectivity Profiling
  • Residence Time Measurements - Determination of koff using 'jump' dilution enzymatic assay method.
  • Mechanism of Action Studies - Kinetic analysis to define the mode of inhibition.
  • Triaging Non-Stoichiometric Inhibitors - Run assays under different conditions such as varying detergent and enzyme concentrations.
  • Evaluate Compound-Target Binding - Run thermal shift assays to confirm compound-target engagement via shifts in melting temperature.

Example Inhibitor Screening & Profiling With Human cGAS

BellBrook scientists performed an inhibitor screening & inhibitor potency profiling of cGAS using the Transcreener cGAMP cGAS Assay.

Inhibitor Screening

Pilot cGAMP Assay Pilot Screen

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. 

Inhibitor Potency Profiling

IC50 of cGAS Inhibitor

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. 

Analysis of Drug-Target Residence Times

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. 

'Jump Dilution' Assay Method

cGAMP Jump Dilution Schematic

Residence Time Measurements

cGAMP Residence Time Measurements for Lead Discovery Services

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.

Triaging Non-Stoichiometric Inhibitors

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). 

Stoichiometric Inhibitor Titrationv2
Non-Stiochiometric Inhibitor Titration lead discovery services

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. 

Thermal Shift Assays Confirm Compound-Target Binding

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.

Thermal Shift Assay Services using 993 Compound

ΔTM = 10°C

Thermal Shift Assay Services using PF-06928215 Compound

ΔTM = 14°C

Choose Your Target

If you don't see your target listed below, please inquire. We may have experience with that target or a similar one within an enzyme family. Click on a target below to learn more. 

Example Target Families
Protein Kinases
Lipid Kinases
Carbohydrate Kinases
ATPases
Acetyltransferases
HDACs
GTPases, GAPs, GEFs
Phosphodiesterases
Helicases
Ligases/Synthetases
Glycosyltransferases

Example Targets
cGAS
AMPK
WRN Exonuclease
CD73
JAK1
WRN Helicase
CD39
JAK3
POLQ
DDX3
EZH2
METTL3/METTL14
ENPP1
PKR
MLL4
IKK-beta
MAPK8
PRMT4
CD38
ADK
PRMT5
PARG
TREX1
RIPK1
TBK1
GALNT2
RIPK2
NSP13
GALNT3
p97
NUDT5
OAS1
KHK

Talk To A Scientist

Let's talk science. We'd like to learn more about your target, your goals, and how we can accelerate your program. 

We'll Do The Work

Send us your compounds. We'll use proven Transcreener Assays to measure enzymatic activity. Assays will be performed in a timely manner at our lab in Madison, WI. 

Quickly Provide a Report & Support

We'll provide a full report including the raw data and results of the experiments. We can keep things as simple or complex as you like. 

Download Our App Note

Transcreener® HTS Assay Overview For Lead Discovery Services

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. 

Transcreener Overview for Drug Discovery Services

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. 

Why Choose BellBrook Labs to Accelerate Your Program?

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 assays and have optimized them for more than 100 different enzyme targets, 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. 

Advantage of BellBrook's Drug Discovery Services

Contact Us to Learn More

Please fill out the form below. We will respond quickly to get the conversation moving and learn how we can help. We keep things discrete, confidential, and professional.

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BellBrook Labs
1232 Fourier Drive, Suite 115
Madison, Wisconsin 53717 USA
(608) 443-2400

info@bellbrooklabs.com

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