Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Wee1 tyrosine kinase is highly expressed in various cancers.
• Wee1 inhibition suppresses tumor cell proliferation and sensitizes cells to DNA-damaging agents.
• AZD1775, a Wee1 inhibitor, causes dose-limiting myelosuppression, including thrombocytopenia.

Purpose of the Study:

• To apply structure-based drug design (SBDD) for generating highly selective Wee1 inhibitors.
• To develop Wee1 inhibitors with improved selectivity against PLK1 compared to AZD1775.
• To evaluate the in vitro antitumor efficacy and toxicity of novel selective Wee1 inhibitors.

Main Methods:

• Structure-based drug design (SBDD) approach.
• Synthesis and characterization of novel Wee1 inhibitors.
• In vitro evaluation of selectivity against PLK1.
• Assessment of in vitro antitumor efficacy and thrombocytopenia induction.

Main Results:

• Rapid generation of highly selective Wee1 inhibitors using SBDD.
• Achieved greater selectivity against PLK1 compared to AZD1775.
• Demonstrated in vitro antitumor efficacy.
• Observed in vitro thrombocytopenia, despite improved selectivity.

Conclusions:

• Selective Wee1 inhibitors were successfully developed via SBDD.
• These inhibitors exhibit in vitro antitumor activity.
• Thrombocytopenia remains a toxicity concern, even with selective Wee1 inhibitors.