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An Internally Controlled Quantitative Target Occupancy Assay for Covalent Inhibitors
Rasmus Hansen1, Sarah J Firdaus2, Shuangwei Li2
1Wellspring Biosciences, Inc., 3033 Science Park Rd., Ste. 220, San Diego, CA, 92121, USA. rasmus@wellspringbiosciences.com.
Scientific Reports
|September 27, 2018
Summary
A new mass spectrometry method quantifies target occupancy for covalent inhibitors without needing untreated controls. This approach was successfully applied to assess the KRASG12C inhibitor ARS-1620.
Area of Science:
- Pharmacology
- Biochemistry
- Analytical Chemistry
Background:
- Target occupancy assessment is vital for evaluating novel inhibitors' efficacy.
- Current clinical methods for target occupancy require untreated controls, posing challenges.
- Covalent inhibitors require robust target engagement confirmation.
Purpose of the Study:
- To develop a novel mass spectrometry method for quantitative target occupancy assessment.
- To enable target occupancy measurement without the need for untreated controls.
- To apply the developed method to a specific KRASG12C inhibitor, ARS-1620.
Main Methods:
- Quantitative mass spectrometry approach.
- Development of a method for target occupancy analysis.
- Application to KRASG12C inhibitor ARS-1620.
Main Results:
- A novel mass spectrometry method was successfully established.
- The method allows quantitative target occupancy assessment without untreated controls.
- The method was validated using the KRASG12C inhibitor ARS-1620.
Conclusions:
- The developed mass spectrometry technique offers a viable alternative for target occupancy assessment.
- This method simplifies the evaluation of covalent inhibitors in clinical settings.
- It facilitates proof-of-mechanism studies and dose determination for novel inhibitors.
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