Innovating Your Drug Discovery

Kinome-wide Profiling of Existing Chemical Assets: A Powerful Strategy to Jump-start New Drug Discovery Programs

Kinase inhibitors are among the fastest growing classes of FDA-approved drugs, and it has been satisfying to see that three have now been approved for non-oncology indications with stringent safety requirements.  As new kinase targets become of interest for both oncology and non-oncology indications, it is critical for drug discovery companies to move quickly since first-in-class drugs showing efficacy are difficult to bypass after approval.

Take Advantage of Existing Kinase Inhibitor Assets for New Programs

One proven strategy for jump-starting new kinase programs is to profile existing kinase-focused chemical assets across the entire kinome.  Although these existing compounds may have initially been designed to target a previous kinase of interest, kinase inhibitors are never perfectly selective and will often have potent activity on a range of additional diverse kinase targets.  Kinome-wide biochemical screens, such as DiscoverX’s KINOMEscan™ service offering, rapidly identify kinases potently “hit” by a compound or compound series and, importantly, also report on the compound’s relative selectivity across the kinome.  This approach enables the identification of “high quality leads” for new kinase targets because it reports on both potency and selectivity – as opposed to single target HTS campaigns, which only report on potency.  High quality leads, which are defined as being both potent and selective, are of the utmost importance when jump-starting a new program since it is difficult and inefficient to start with a potent but non-selective inhibitor and to then dial-in selectivity while maintaining potency.  And once these screens have been performed, the dataset becomes an invaluable resource for future queries as additional kinases become of interest.

Examples of Successful Kinome-wide Screening Campaigns

Multiple successful kinase inhibitor discovery strategies incorporating KINOMEscan screens have been executed in the past several years.  Some of these approaches involved screening thousands of molecules – and some involved screening tens or hundreds.  Regardless of the scale of the screening initiative, valuable high quality starting points for inhibitor discovery were always identified.

#1 – Ambit Biosciences

During my early years at Ambit Biosciences all we really had was a smaller version of the current KINOMEscan panel and a modest collection of pre-clinical, clinical, and approved reference kinase inhibitors (<50 compounds).  Our strategy was to screen these reference kinase inhibitors across the entire kinase panel and to identify any potent “off-target” kinases that may be compelling candidates for new drug discovery campaigns.  We found that FLT3 was a potent off-target of an otherwise reasonably selective reference compound, and this finding jump-started a successful program that culminated in the discovery of quizartinib, a highly potent and selective FLT inhibitor currently in Phase III clinical trials for AML.  And this same strategy self-propagated – every medicinal chemistry compound we made internally was screened across the kinome, which resulted in high quality leads and successful programs focused on BRAF, JAK2, and CSF1R.  And all of this was possible without ever having the need to purchase a chemical library – we simply squeezed as much value out of every existing chemical asset as possible.

#2 – Janssen

KINOMEscan annotation of kinase-focused compound collection (3,400 compounds) resulted in high quality starting points for programs in six disease areas and high quality leads for over 130 kinases (1).

#3 – Bristol Myers Squibb

KINOMEscan annotation of a kinase-focused compound collection (>20,000 compounds) provided valuable insight into kinase druggability, features of selective kinase inhibitors, and paradigms for designing efficient kinase-focused screening collections (2).

#4 – Blueprint Medicines

KINOMEscan successfully annotated Blueprint’s proprietary compound library to accelerate lead identification.

“The ability to characterize the diverse collection of kinase inhibitors in our proprietary compound library provides us with unique insights into the potency and selectivity of a potential drug candidate early in the discovery process, helping us accelerate lead identification,” said Tim Guzi, Blueprint Medicines’ Vice President of Chemistry. Read full Press Release.

#5 – The Structural Genomics Consortium (SGC)

An ongoing collaboration with KINOMEscan to screen the Published Kinase Inhibitor Sets (PKIS) with the goal of developing potent and selective probes for the 85 percent of kinases that traditionally have been understudied. Read full Press Release.

High quality starting points for probe development for understudied kinases have already been reported (3).

Jump Start New Kinase Programs

To identify potential new kinase programs using your existing compound asset library, learn more about the DiscoverX KINOMEscan kinase profiling service, the largest kinase screening panel on a single assay platform.

  1. Jacoby E, et al. Extending Kinome Coverage by Analysis of Kinase Inhibitor Broad Profiling Data. Drug Discovery Today. 2015 Jun, 20(6):652-8.
  2. Posy SL, et al. Trends in Kinase Selectivity: Insights for Target Class-focused Library Screening. J Med Chem. 2011 Jan 13;54(1):54-66.
  3. Elkins JM, et al. Comprehensive Characterization of the Published Kinase Inhibitor Set. Nat Biotechnol. 2016 Jan;34(1):95-103.