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Discovery of ZSL-M028: A Potent, Selective and Orally Available Quinazoline-Based PLK4 Inhibitor Targeting
Nian Liu1, Zehui Qi1, Wenqiang Sun1
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang110016, PR China.
Abstract:
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 (IC50 = 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.
Insights
A novel quinazoline-based compound, M028, effectively inhibits Polo-like kinase 4 (PLK4), showing promise for treating TRIM37-amplified neuroblastoma. This targeted therapy demonstrates significant antitumor activity and a favorable safety profile.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Polo-like kinase 4 (PLK4) is a key regulator of centrosome duplication and a therapeutic target in cancer.
- Synthetic lethality between PLK4 inhibition and TRIM37 amplification presents a targeted treatment strategy for specific tumors.
- Existing PLK4 inhibitors lack structural diversity, limiting therapeutic development.
Purpose of the Study:
- To develop novel, structurally diverse PLK4 inhibitors using structure-guided scaffold-hopping and fragment growth.
- To identify and optimize a lead compound for treating TRIM37-amplified cancers, specifically neuroblastoma.
Main Methods:
- Employed structure-guided scaffold-hopping and fragment growth strategies to design new quinazoline-based PLK4 inhibitors.
- Optimized compound B33 (ZSL-M028) for potent PLK4 inhibition, selectivity, and pharmacokinetic properties.
- Evaluated in vitro and in vivo antitumor activity and safety profile of M028 in TRIM37-amplified neuroblastoma models.
Main Results:
- The optimized compound M028 demonstrated potent PLK4 inhibition (IC50 = 1.1 nM) and high selectivity over Aurora A kinase (>1600-fold).
- M028 exhibited favorable ADME and pharmacokinetic properties, including 55.4% oral bioavailability.
- Significant in vitro and in vivo antitumor efficacy was observed in TRIM37-amplified neuroblastoma, with a good safety profile.
Conclusions:
- M028 represents a promising novel quinazoline-based inhibitor of PLK4.
- This compound shows potential as a precision therapy for TRIM37-amplified neuroblastoma.
- The findings offer new therapeutic opportunities for specific cancer types driven by TRIM37 amplification.