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Published on: February 23, 2024
Wee1-targeting inhibitors: From virtual screening to lead discovery
Jochem Nelen1, Bidisha Sarkar2, Javier Jiménez-Bernad3
1Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), HiTech Innovation Hub, UCAM Universidad Católica de Murcia, Murcia 30107, Spain; Health Sciences PhD Program, Universidad Católica de Murcia UCAM, Campus de los Jerónimos n°135, Guadalupe, Murcia 30107, Spain.
New Wee1 inhibitors were identified through virtual screening and synthesis. Analog 20 demonstrated potent inhibition of cancer cell proliferation, showing promise as a lead candidate for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Discovery
Background:
- Wee1-like protein kinase (Wee1) is a validated target for cancer therapy.
- No Wee1 inhibitors have yet received regulatory approval, highlighting the need for new drug candidates.
Purpose of the Study:
- To identify novel Wee1 inhibitors with improved potency and selectivity.
- To explore structure-activity relationships (SAR) and optimize lead compounds.
- To evaluate the drug-likeness and potential of identified inhibitors as cancer therapeutics.
Main Methods:
- Virtual screening of the Eurofins-Villapharma library to identify initial Wee1 inhibitors.
- Synthesis and biochemical testing of analogs to improve potency.
- Cellular assays to assess proliferation inhibition in various cancer cell lines.
- Kinome screening for selectivity profiling.
- Molecular dynamics simulations for binding interaction analysis.
- In vitro ADME profiling for physicochemical properties.
Main Results:
- Compound 1 (IC50 = 240 nM) was identified as an initial hit.
- Analog 20 exhibited significantly improved potency (IC50 = 33 nM) and inhibited proliferation of lung, ovarian, and breast cancer cell lines (IC50s ranging from 0.449 to 0.842 μM).
- Compound 18 showed selectivity in kinome screening (S(1) score = 0.025) with weaker cellular activity.
- SAR analysis identified key determinants for activity, and molecular dynamics simulations supported binding interactions.
- In vitro ADME profiling indicated favorable physicochemical properties and drug-likeness.
Conclusions:
- Analog 20 is a potent Wee1 inhibitor with significant anti-proliferative activity across multiple cancer cell lines.
- Compound 18 demonstrates selectivity, suggesting potential for targeted therapy.
- The identified compounds possess favorable drug-like properties, supporting their development as lead candidates for cancer treatment.
