First-in-Class Quinoline-Dione-Derived PROTACs: Potent Degraders of Cdc25 Phosphatases for Antitumor Therapy

Dysregulated Cdc25 phosphatases drive tumorigenesis,
but their
“undruggable” active site (planar and electropositive)
has hindered small-molecule inhibitor development. Herein, we report
the first-in-class PROTAC degraders targeting Cdc25, derived from
the quinoline-dione scaffold, by conjugating NSC663284 (a Cdc25 inhibitor) with E3 ligase ligands via optimized linkers.
Among them, compound D3, the most potent degrader, induced
concentration- and time-dependent degradation of Cdc25A/B/C with DC50 values of 0.97 μM, 2.02 μM, and 4.67 μM,
respectively, via a proteasome-dependent pathway. D3 can
significantly inhibit tumor growth in xenotransplantation models and
exhibit a favorable pharmacokinetic profile. Mechanistically, D3 exerts antitumor effects by degrading the target protein
Cdc25, upregulating p-CDK1/2 levels, and subsequently inducing G2/M phase cell cycle arrest and apoptosis. This study validates
PROTACs as a breakthrough strategy to target “undruggable”
Cdc25, provides a novel quinoline-dione-based scaffold for antitumor
drug development, and offers a rational design paradigm for tackling
intractable phosphatase targets.