Discovery of ZSL-M028: A Potent, Selective and Orally Available Quinazoline-Based PLK4 Inhibitor Targeting <i>TRIM37</i> -Amplified Neuroblastoma

Polo-like kinase 4 (PLK4), a master regulator of centrosome duplication, has emerged as an attractive therapeutic target in oncology. Notably, the synthetic lethality between PLK4 inhibition and TRIM37 amplification provides a strong rationale for targeted tumor intervention. However, the limited structural diversity of current PLK4 inhibitors constrains further development. Herein, structure-guided scaffold-hopping and fragment growth strategies were employed to develop a series of structurally novel quinazoline-based PLK4 inhibitors. The optimized compound B33 ( ZSL-M028 ) exhibited potent PLK4 inhibition (IC 50 = 1.1 nM), excellent selectivity over Aurora A kinase (over 1600-fold), and favorable ADME and pharmacokinetic properties, including an oral bioavailability of 55.4%. M028 further demonstrated significant in vitro and in vivo antitumor activity against TRIM37 -amplified neuroblastoma with a favorable safety profile. Overall, M028 represents a promising lead for PLK4 inhibition, and offers new opportunities for precision therapy in TRIM37 -amplified neuroblastoma.