Innovating Your Drug Discovery

Biological Validation of the BioMAP® Platform with Phenotypic Chemical Probes

Phenotypic chemical biology is the use of target-selective chemical probes and drugs in cell-based or in vivo assays for establishing target function and disease relevance. Last year we began an initiative with SGC’s Chemical Probes Portal to develop a chemical probe collection suitable for characterizing phenotypic screens. The results of this effort have now been published online in Drug Discovery Today: Technologies (Phenotypic Chemical Biology for Predicting Safety and Efficacy, 2017).

The idea was to develop a small set of probes to help researchers in assay development using 2D, 3D and even organs-on-a-chip validate their assays for a common set of target and pathway mechanisms. In vitro phenotypic assays are used in drug discovery as well as for toxicology and alternative methods research, thus a standard set of probes would facilitate assay cross-comparison.

For this effort, we leveraged DiscoverX’s BioMAP platform, the leading human primary cell-based profiling technology with the broadest coverage of tissue biology, pathways and mechanisms.  Using profiles from the BioMAP Reference Database, we have compiled a list of seventeen selected chemical probes that are suitable for characterizing and validating phenotypic screens. These 17 probes represent the best of the best, covering a broad range of pathway and target mechanisms with probes that are potent and selective for their targets or target class.

These select chemical probes also cover pathways that are of interest in phenotypic drug-discovery (PDD) campaigns as they include compounds selective for common off-targets. These probes are well known, and many are approved drugs, facilitating the connection of assay results to clinical effects. All of the probes on this list have been profiled across the Diversity PLUS™ panel of human primary cell-based model systems. They are active and well-behaved across a wide range of concentrations (a feature we call “dose-resistance”, which is a characteristic of highly selective compounds and many approved drugs).

We hope that the development of a standard set of probes for phenotypic screens will inspire the community and create wide acceptance of criteria for phenotypic assays. Characterizing phenotypic assays with this set of probes will help researchers more quickly deconvolute the mechanisms of any hits. More importantly, the results of testing and sharing these data will help us better understand mechanisms of disease biology.

The Phenotypic Probe List:

Compound  (Mechanism)

GDC-0941  (PI3K Inhibitor)

JQ1 (BET Inhibitor)

Rapamycin (mTOR Inhibitor)

Tofacitinib  (JAK Inhibitor)

VX-745  (p38 MAPK Inhibitor)

8-CPT-cAMP (PKA/PKG Activator)

Atorvastatin (HMG-CoA reductase Inhibitor)

Colchicine (Microtubule Inhibitor)

Concanamycin A (V-type ATPase Inhibitor)

GF 109203X (PKC (c+n) Inhibitor)

Vorinostat (HDAC Inhibitor)

Oligomycin A (Mitochondrial Inhibitor)

Phorbol 12-myristate 13-acetate (PKC Activator)

Prednisolone (GR Agonist)

R(-) Rolipram (PDE IV Inhibitor)

Tacrolimus / FK-506 (Calcineurin Inhibitor)

Trametinib (MEK Inhibitor)