Case Studies
Kinase Expertise, Industry Experience, Proven Results
The last decade has seen a significant increase in the understanding of kinase biology, and corresponding investments in kinase-focused drug discovery. However, despite many successes, developing successful therapeutics with the right balance of selectivity and potency remain challenging, costly and time consuming with no guarantee of success. As development of kinase inhibitors continues to expand to therapy areas beyond oncology, novel strategies and perspicacious judgment must be exercised to maximize positive outcomes.
KINOME
scan partners with biotechnology and pharmaceutical organizations to help them extract the most value out of their kinase-focused chemistry assets and has demonstrated success in accelerating drug discovery from lead discovery to delivering clinical candidates. The case studies below show how KINOME
scan can help customers overcome screening bottlenecks, keep programs on track and on budget, and support lead optimization to guide selection of superior clinical candidates.
- Unlock the full potential of kinase-focused libraries
- Enable decision making based on biology and chemistry
- Focus resources on programs most likely to succeed
- Respond quickly to new target discoveries with advanced launch points
- Reveal opportunities and expand therapeutic utility of existing compounds
Selected Case Studies and Technical Notes
High-throughput Kinase Profiling as a Platform for Drug Discovery
A Paradigm Shift in Kinase Drug Discovery Strategy
In the traditional drug discovery model, a kinase target is typically chosen based on biology alone. A large chemical library is screened for potency against the single target and hits are then optimized to achieve the desired potency and selectivity that meets criteria for a drug-like clinical candidate.
The advent of kinome-wide library profiling harnesses both chemical and biological data to inform program decisions and direct investment into the best discovery programs accessed by the library in question. This alternative strategy is increasingly being used to improve drug discovery efficiency and the likelihood of clinical success. (cf. publications -
BMS library screen,
GSK library screen,
Perspectives) Prior to selecting a particular target, a kinase-biased subset of compounds is profiled against a broad panel of kinases and is fully annotated for both potency and selectivity against the majority of the kinome. With full knowledge of both potency and selectivity for every compound in the library, informed decisions about which targets to pursue.
Paradigms in Drug Discovery
In contrast to the traditional and largely linear kinase inhibitor discovery model in which one kinase target is assessed at a time, KINOMEscan affords the unprecedented ability to comprehensively screen entire compound collections against large panels of kinases. This highly parallel approach enables organizations to identify multiple targets of interest, defined by target biology, for which high quality 'lead like' compounds exist and to focus resources on those programs most likely to succeed [click graph to enlarge].
Benefits
- Begin programs with high-quality lead-like compounds
- Identify targets of interest most accessible with existing chemistry
- Respond quickly to novel kinase targets of interest
- Focus resources on programs most likely to succeed
Results
Quizartinib (AC220), a potent, highly selective, orally bioavailable second-generation FLT3 inhibitor recently entered a pivotal trial that may support approval as a monotherapy treatment for adult patients with relapsed/refractory acute myeloid leukemia. This candidate went from concept to lead candidate selection in only 18 months, and emerged as a direct result of identifying targets of interest from a biological perspective most readily accessed by available compounds. Additionally, KINOME
scan drove the identification and optimization of AC430, a JAK2 inhibitor, and has created a robust pipeline of preclinical candidates.
Simplify Lead Optimization: Leverage the Benefits of Outsourced Custom Panel Profiling
Opportunity
Customer used an in-house 48 kinase panel for lead optimization compounds and
scanMAX for select compounds and benchmark analysis. Internal customer resource challenges coupled with limited program support resulting from small kinase panel were overcome using portfolio of available KINOME
scan assays and weekly turnaround.
- 0.5 FTE devoted to weekly lead optimization screening.
- Limitations due to limited assay availability with existing screening solution.
Solution: Custom Panel
| Feature |
Customer In-house Panel |
KINOMEscan Custom Panel |
| Full Time Equivalent (FTE) |
0.5 |
0 |
| No. of Assays |
48 (219) |
100 (451) |
| Turnaround time |
1 week |
1 week |
| Cost |
Same |
Same |
Customer Benefit
- Customer replaced 48 assay in-house kinase panel with an outsourced 100 assay custom panel from KINOMEscan for the same cost with one week turnaround.
- Additional assays provided enhanced support to existing programs and provided support to additional programs.
- Platform consistency between custom panel and scanMAX.
- Customer reallocated FTE to higher value discovery activities.
Harnessing Selectivity and Toxicology in Lead Optimization
In vivo Tolerability Study Reveals Unanticipated Toxicity
Kinome-wide profiling was employed in a lead discovery program and successfully identified a high quality lead for optimization. During lead optimization customer initiated short term
in vivo tolerability study and confirmed anticipated primary target mediated pharmacodynamic (PD) effect, but also revealed unanticipated gastrointestinal toxicity. Although observed GI toxicity could have been related to the novel and uncharacterized primary target, selectivity data identified Aurora kinase as an off-target and potential liability, reported to induce similar GI changes.
Extended Pharmacology Supports PD Effect
Anticipated primary-target pharmacodynamic effect in short term in vivo tolerability study of Compound A. Extended pharmacology results in mild bone marrow hypocellularity (high magnification, bottom panels) [click graph to enlarge].
Toxicity: Primary Target or Off-Target Kinase?
Gastrointestinal lesions highlight target organ in short term in vivo tolerability study of Compound A. Marked villous atrophy and abnormal epithelium in treated rat duodenum (high magnification, bottom panels) [click graph to enlarge].
Identification of a Superior Compound
The chemical series was interrogated for an alternative compound lacking off-target liability. Selectivity database revealed Compound B with properties similar to Compound A but diminished affinity for the Aurora kinases. Short-term
in vivo tolerability studies were initiated for Compound B, which confirmed bone marrow hypocellularity (anticipated PD effect) with unremarkable GI tissue, consistent with the elimination of off-target liability and superior clinical candidate.
Comparison of Compound Potency
Selectivity database revealed Compound B, an analog of Compound A, with similar properties but diminished affinity for off-target Aurora kinases [click graph to enlarge].
Confirmation of in vivo Tolerability
In vivo tolerability study of Compound B showing bone marrow hypocellularity (PD effect) and unremarkable GI tissue. Selectivity profile confirms Aurora kinase off-target liability in Compound A. Diminished Aurora kinase affinity in Compound B eliminates off-target liability and gives rise to a superior clinical candidate [click graph to enlarge].
Customer Benefit
Broad selectivity information gained from previous lead discovery activities enabled customer to understand off-target liabilities and provided program team with necessary information to interpret potential toxicity-MOA data leading to the immediate selection of superior candidate.