Discovery of Naphthyridinone Derivatives as Selective PKMYT1/WEE1 Dual Inhibitors for Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• PKMYT1 and WEE1 are key G2/M checkpoint kinases regulating CDK1 phosphorylation.
• Dual inhibition is a potential strategy for tumors with G1/S checkpoint defects and high replication stress.

Purpose of the Study:

• To design and optimize novel dual inhibitors of PKMYT1 and WEE1 kinases.
• To evaluate the efficacy and safety of a lead compound in preclinical cancer models.

Main Methods:

• Structure-based drug design and synthesis of 1,7-naphthyridinone derivatives.
• Biochemical assays (NanoBRET) for kinase inhibition and cellular assays for target engagement (pCDK1 T14/Y15).
• Kinome profiling, organoid efficacy studies, and in vitro ADME/safety assessments.

Main Results:

• Compound 24 exhibited potent inhibition of PKMYT1 (nM) and WEE1 (sub-μM) with high selectivity.
• 24 effectively reduced pCDK1 T14 and Y15 phosphorylation in cancer cells.
• In colorectal cancer organoids, 24 demonstrated superior efficacy compared to existing inhibitors and favorable in vitro ADME/safety.

Conclusions:

• Compound 24 is a potent dual PKMYT1/WEE1 inhibitor with a promising preclinical profile.
• Dual checkpoint targeting represents a viable therapeutic strategy for checkpoint-deficient cancers.
• Further development of 24 is warranted for clinical investigation.