Compound Screening Cascade
Compound Screening Cascade
Reaction Biology excels in its capability of compound screening. As the industry leader, we offer the largest portfolio of established assays, including testing of enzymatic activity, binding assays, protein-protein interactions, biophysical binding, electrophysiology, and cell-based receptor functions. Together with our chemistry partners, our scientists will work with you to create the compound screening cascade best suited for your drug discovery program.
Advantage of the Reaction Oncology Platform:
- Our ambition to use gold-standard assay formats whenever possible ensures high-quality screening results in all steps of the compound screening cascade.
- Our scientists bring many years of experience in targeted drug discovery, granting smooth operations with our medicinal chemistry and ADME partners for low cycle time and optimal results.
- We help you select the right assays to gain insight into the structure-activity relationship together with the medicinal chemistry team.
Assay Formats for primary, orthogonal, and secondary screening
Each drug discovery project needs a different set of assays including (i) finding primary hits via high-throughput screening, (ii) confirming hits by IC50 value determination in biochemical assay formats, (iii) using orthogonal screening to identify false positives/negatives, (iv) perform counter assays to validate the screening results, (v) probe the mode of action to ensure on-target effects, (vi) evaluate the binding affinities and (vii) kinetics both outside and inside cells.
Rapid analog synthesis
Wherever possible, Symeres employs parallel synthesis tools for the preparation of analog sets that allow for the expedient generation of structure-activity relationships. Library synthesis is a core competency of Symeres and our organization generates tens of thousands of molecules every year using parallel reactor, purification, and analytical systems.
Airtight: Kinase inhibitor discovery assays - Example 1
Performing kinase inhibitor screening using the most comprehensive kinase assay portfolio in the industry
Primary high-throughput screening and IC50 dose-response studies are performed with the gold standard radioactive kinase assays to test kinase activity. Our two independent research sites offer the option for orthogonal screening to identify false-positive results. The interpretation of the results is aided by testing of binding affinities or kinetic parameters via biophysical methods. Integral for every kinase inhibitor discovery program is selectivity testing since the catalytic sites of kinases have a high resemblance. Selectivity profiling at Reaction Biology can be performed early in the process with 2-point readouts and later in the project with 10-point IC50 value readouts for an accurate selectivity profile. Our two cellular kinase assays, NanoBRET Assay and Cellular Phosphorylation Assay give valuable insight into the compound-target interaction in the physiological environment of intact cells.
Targeting the undruggable - Example 2
A suite of assays for the discovery of novel Ras pathway inhibitors
Ras is targeted via numerous strategies: inhibition of Ras' GTPase activity, interruption of the interaction to key players such as SOS1, inhibition of downstream signaling events, and more. Reaction Biology has created a suite of assays to investigate compounds targeting Ras and the Ras pathway.
Iterative Compound Screening Cycle – Example 3
Setup of an iterative compound screening program for SAR optimization of a kinase inhibitor
To support the medicinal chemistry phase for a new hit series we needed to perform weekly to bi-weekly screening of 15 to 20 compounds to determine the activity of the compounds in both biochemical assays and cellular assays.
A screening cascade was set up to determine IC50 values for the compounds in three assays within one week or two weeks to facilitate fast turnaround times for medicinal chemistry optimization. Chemists may test basic parameters such as the solubility of new compound series.
Every three months, an extended cycle is performed based on the progress of the discovery project. The additional assays may include selectivity screening on a large kinase panel, a counter assay, determination of the binding affinity, testing of PK parameters in mice, hERG binding, and others.