Reaction Signals Q4 2026 Newsletter
Headlines In This Issue
Featured Research
InVEST44™ flagged off-target liabilities in 17 of 20 oncology candidates pulled from trials for severe adverse effects.
Scientific Spotlight
The two papers behind every InVEST™ panel, and how to choose the right tier.
Industry Insights
Three papers on why off-target pharmacology still decides who survives the clinic.
New at Reaction Biology
A cell viability add-on, tiered cardiac safety and 14-isoform CYP450 profiling.
Important Dates
Screening deadlines through March 2027, and where to meet us through AACR 2027.
Featured Research
InVEST44™ Is a Cost-Effective In Vitro Safety Panel That Identifies Off-Target Effects in Early-Stage Drug Discovery
Wooltorton JR, et al. | AACR 2026
A new drug costs $172.7M to develop, or $515.8M once failed candidates are counted. Yet early-stage work, including in vitro safety, fell from 50% of biopharma venture funding in 2006 to 16% in 2023.
Our In Vitro Safety team asked a direct question: would an early safety panel have caught what ended these trials?
- $515.8M per new drug, counting failed candidates
- 17 of 20 flagged by InVEST44™
- 12 of 20 flagged by Diversify™ kinases
Study design: 20 oncology candidates terminated for severe adverse effects (2001 to 2025), screened at 10 µM against the 44 targets in InVEST44™ and the 70 kinases in Diversify™.
InVEST44™
- 17 of 20 hit at least one safety target
- 8 hit four or more
- One hit 15
Diversify™ kinases
- 12 of 20 hit at least one kinase
- 5 hit four or more
- One hit 18
Targets with >50% effect at 10 µM, per candidate.
Why it matters for your program: every one of these liabilities was measurable in vitro, before animals or patients. A 44-target screen costs a fraction of a terminated trial and gives your chemists time to design around the problem.
Download the AACR 2026 poster →
Scientific Spotlight
The Two Papers Behind Every InVEST™ Panel
Regulators require hERG data before first-in-human dosing, but not which other off-targets to screen. Two Nature Reviews Drug Discovery papers, 12 years apart, set that standard.
2012 | Bowes et al.: the original 44
AstraZeneca, GSK, Novartis and Pfizer agreed on 44 targets with clear links to clinical adverse drug reactions, weighted toward GPCRs and ion channels. The premise: about 75% of ADRs are dose-dependent and predictable from pharmacology, so they can be caught in vitro.
InVEST44™ is the Bowes panel: 24 GPCRs, 8 ion channels, 6 enzymes, 3 transporters, 2 nuclear receptors and 1 kinase.
2024 | Brennan et al.: the modern consensus
A survey of 18 IQ DruSafe companies confirmed early off-target screening as standard practice and proposed 77 targets that reflect portfolios moving toward kinases. A 2025 follow-up flagged non-kinase enzymes, including cathepsins, as still underrepresented.
InVEST18™, InVEST33™, InVEST59™ and InVEST77™ are built on the Brennan sets. Compared with InVEST44™, InVEST77™ adds:
- Kinases: 1 to 20, all at physiological 1 mM ATP
- Nuclear receptors: 2 to 5 (ERα, PR, RARα)
- GPCRs: 24 to 30 (including MRGPRX2, 5-HT6, NK3)
- New classes: cathepsin D, MALT1 and BRD4
Choosing the Right Tier
- InVEST18™: Hit-to-lead triage on the highest-risk targets, including hERG
- InVEST44™: The Bowes standard, ICH S7A/B aligned
- InVEST59™: Kinase-expanded selectivity for SAR. Run after InVEST18™ to complete InVEST77™.
- InVEST33™: Run after InVEST44™ to complete InVEST77™.
InVEST77™, the full profile: the complete Brennan-aligned profile for candidates heading toward IND-enabling studies. Run it directly, or build to it from a panel you have already run:
- InVEST18™ + InVEST59™ = InVEST77™
- InVEST44™ + InVEST33™ = InVEST77™
Every tier: 10 business day turnaround, monthly runs, screening at 10 µM or a client-requested concentration, functional readouts (FLIPR, cell reporter, manual patch clamp) that separate agonists from antagonists, and 8-point concentration-response curves only on flagged hits.
Explore the InVEST™ safety panels →
Industry Insights
About 90% of clinical candidates fail, and roughly 30% of those failures are unmanageable toxicity (Sun et al., 2022). Three papers on why off-target pharmacology still decides who survives the clinic:
Off-Target Toxicity Is a Common Mechanism of Action of Cancer Drugs Undergoing Clinical Trials
Knocking out the reported targets of 10 clinical-stage cancer drugs did not stop them killing cancer cells. Their activity was off-target. If a mechanism can be wrong this late, so can a liability profile.
Read the paper in Science Translational Medicine →
A Preclinical Secondary Pharmacology Resource Illuminates Target-Adverse Drug Reaction Associations of Marketed Drugs
Novartis profiled 1,958 drugs across 200 assays and linked specific off-targets to the adverse reactions seen in patients, showing which hits carry real clinical risk.
Read the paper in Nature Communications →
The State of the Art in Secondary Pharmacology and Its Impact on the Safety of New Medicines
The 18-company IQ DruSafe review behind the 77-target standard. Its 2025 follow-up calls for more enzyme coverage: InVEST33™, InVEST59™ and InVEST77™ already include cathepsin D and MALT1.
Read the paper in Nature Reviews Drug Discovery →
New at Reaction Biology
Cell Viability for InVEST™ Panels
Running InVEST33™, InVEST44™, InVEST59™ or InVEST77™? Add HEK293 and CHO cell viability (single concentration, in duplicate, 22 to 24 hours) to the same submission. Results arrive with your panel data.
Add cell viability to your next run →
Cardiac Safety, From Ion Channel to Whole Heart
hERG-only screening can overstate proarrhythmic risk when other channels offset it. Match the assay to the stage:
- hERG FP binding for early triage
- Manual patch clamp (hERG, NaV1.5, CaV1.2, KCNQ1) at room or physiological temperature
- CiPA core panel (hERG, NaV1.5, CaV1.2) for multi-channel risk
- Purkinje fiber and Langendorff isolated heart for tissue- and organ-level ECG
Learn more about cardiac safety assessment →
InVEST™ CYP: 14 CYP450 Isoforms
FDA, EMA and ICH M12 require in vitro CYP inhibition data before clinical trials. InVEST™ CYP covers 14 isoforms, including the seven major drug-metabolizing enzymes, with reversible and time-dependent inhibition at 10 µM or 10-point IC50, in 10 business days.
Learn more about CYP450 inhibition assays →
Upcoming Screening Schedule
Ensure your compounds are included in our upcoming screening runs.
Please note the following deadlines for sample submission through March 2027.
Request a quote for compound screening →
| InVEST18/33/44/59/77 Safety Panels | December 11 | January 8 | February 5 | March 5 |
| Bromodomain Full Panel | December 4, 31 | January 29 | February 26 |
| Protease Full Panel | December 24 | January 22 | February 19 | March 19 |
| Phosphodiesterase (PDE) Full Panel | December 18 | January 22 | February 19 | March 19 |
| ProLiFiler™ Cancer Cell Panel | December 30 | February 12 |
| Histone Deacetylase (HDAC) Full Panel | December 4 | January 8 | February 5 | March 5 |
| Methyltransferase Full Panel | December 4, 31 | January 15, 29 | February 12, 26 | March 12 |
| Kinase Panel Screening (US Facility) | |
|---|---|
| Full Panel | December 2, 30 | January 13, 27 | February 10, 24 | March 10, 31 |
| 1 mM ATP (Wildtype, Mutant, Atypical, Lipid, and Diacylglycerol) | December 16 | January 20 | February 17 | March 17 |
| Diversify Panel | December 9 | January 6 | February 3 | March 3 |
| Kinase Panel Screening (German Facility) | |
|---|---|
| Full Panel (Wild Type, Mutant, Diversify, Lipid) | November 26 | January 7 | February 4 | March 4 |
Conferences and Events
PharmaLab
- Düsseldorf, Germany | November 24-26 | Booth #54
- Talk: Potential Cell-Based Alternatives to Animal Potency Tests: From BaF3-EpoR and FSHR-cAMP to LinkLight® (Jan Ehlert)
Tumor Models London
- London, UK | December 2-3
NextGen Biomed
- London, UK | March 18-19, 2027
AACR Annual Meeting
- Orlando, FL | April 2-7, 2027
About Reaction Biology
A partner that reduces risk at every milestone
For 25 years, we have delivered reliable, timely data to 2,500+ clients and supported hundreds of IND submissions. Four sites across the US and Europe cover biochemical, cellular, biophysical, safety and in vivo work under ISO 9001:2015 quality management.
Let’s discover together.
References
Bowes, J., Brown, A. J., Hamon, J., Jarolimek, W., Sridhar, A., Waldron, G., & Whitebread, S. (2012). Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nature Reviews Drug Discovery, 11(12), 909-922. https://doi.org/10.1038/nrd3845
Brennan, R. J., Jenkinson, S., Brown, A., Delaunois, A., Dumotier, B., Pannirselvam, M., et al., & Valentin, J.-P. (2024). The state of the art in secondary pharmacology and its impact on the safety of new medicines. Nature Reviews Drug Discovery, 23(7), 525-545. https://doi.org/10.1038/s41573-024-00942-3
Lin, A., Giuliano, C. J., Palladino, A., John, K. M., Abramowicz, C., Yuan, M. L., et al., & Sheltzer, J. M. (2019). Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine, 11(509), eaaw8412. https://doi.org/10.1126/scitranslmed.aaw8412
Schmidt, F., Brennan, R. J., Jenkinson, S., & Valentin, J.-P. (2025). Shaping secondary pharmacology panels of the future: evolving target selection criteria for safety panels. Nature Reviews Drug Discovery. https://doi.org/10.1038/s41573-025-01184-7
Sertkaya, A., Beleche, T., Jessup, A., & Sommers, B. D. (2024). Costs of drug development and research and development intensity in the US, 2000-2018. JAMA Network Open, 7(6), e2415445. https://doi.org/10.1001/jamanetworkopen.2024.15445
Sun, D., Gao, W., Hu, H., & Zhou, S. (2022). Why 90% of clinical drug development fails and how to improve it? Acta Pharmaceutica Sinica B, 12(7), 3049-3062. https://doi.org/10.1016/j.apsb.2022.02.002
Sutherland, J. J., Yonchev, D., Fekete, A., & Urban, L. (2023). A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs. Nature Communications, 14, 4323. https://doi.org/10.1038/s41467-023-40064-9
Wooltorton, J. R., Ahona, A. M., Barbacane, N., D’Andrea, A., Lansberry, J. R., Lay, C., Miller, P., Ries, J., Steffen, J., & Valentine, P. A. (2026). InVEST44 is a cost-effective in vitro safety panel that identifies off-target effects in early-stage drug discovery [Poster]. AACR Annual Meeting 2026.
