Design, synthesis, and biological evaluation of 5-chlorine-2-amino-pyrimidine derivatives as potent PLK4 inhibitors
Shuyi Mu1, Wenqiang Sun1, Zehui Qi1
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District Shenyang 110016 PR China medchemzhao@163.com.
Abstract:
Serine/threonine kinase PLK4, a critical regulator of centrosome duplication, is closely associated with tumorigenesis due to its role in centrosome amplification. PLK4 is overexpressed in multiple cancers and has recently emerged as a promising therapeutic target for TRIM37-amplified breast cancer. Developing safe and effective PLK4 inhibitors holds significant therapeutic potential. However, currently reported PLK4 inhibitors face challenges such as limited structural diversity and potential safety concerns. Here, we designed a series of amino-pyrimidine-based PLK4 inhibitors using a structure-activity relationship (SAR)-guided strategy. Half of these compounds exhibited potent PLK4 inhibition (IC50 < 10 nM), with three compounds showed significant anti-proliferative activity against TRIM37-amplified MCF-7 cells (IC50 < 1 μM). Compound 5f demonstrated more exceptional potency (PLK4 IC50 = 0.8 nM; MCF-7 IC50 = 0.48 μM), along with favorable plasma binding and liver microsomal stability. Further evaluation in MCF-7 cells revealed its ability to suppress clonogenic survival, induce mitotic arrest, and trigger apoptosis. These findings highlight 5f as a promising PLK4 inhibitor warranting further investigation.
Insights
Researchers developed novel amino-pyrimidine compounds targeting Polo-like kinase 4 (PLK4), a key driver in cancer. Compound 5f shows potent inhibition and anti-cancer effects, offering a promising therapeutic candidate for breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Polo-like kinase 4 (PLK4) is crucial for centrosome duplication and implicated in tumorigenesis via centrosome amplification.
- PLK4 overexpression is observed in various cancers, making it a potential therapeutic target, particularly in TRIM37-amplified breast cancer.
- Existing PLK4 inhibitors lack structural diversity and raise safety concerns, necessitating the development of new agents.
Purpose of the Study:
- To design and synthesize novel amino-pyrimidine-based inhibitors of PLK4.
- To evaluate the inhibitory activity and anti-proliferative effects of these compounds against cancer cells.
- To identify a potent and safe PLK4 inhibitor for further preclinical development.
Main Methods:
- Structure-activity relationship (SAR)-guided design and synthesis of amino-pyrimidine derivatives.
- In vitro enzymatic assays to determine PLK4 inhibition potency (IC50).
- Cell-based assays to assess anti-proliferative activity against MCF-7 breast cancer cells and evaluate cellular effects like apoptosis and mitotic arrest.
Main Results:
- Several synthesized compounds demonstrated potent PLK4 inhibition with IC50 values below 10 nM.
- Three compounds exhibited significant anti-proliferative activity against TRIM37-amplified MCF-7 cells (IC50 < 1 μM).
- Compound 5f displayed exceptional potency (PLK4 IC50 = 0.8 nM, MCF-7 IC50 = 0.48 μM), good plasma binding, and liver microsomal stability, effectively suppressing cell survival, inducing mitotic arrest, and promoting apoptosis.
Conclusions:
- The designed amino-pyrimidine compounds represent a promising new class of PLK4 inhibitors.
- Compound 5f is a highly potent PLK4 inhibitor with favorable drug-like properties and significant anti-cancer activity in vitro.
- Compound 5f warrants further investigation as a potential therapeutic agent for PLK4-driven cancers, including TRIM37-amplified breast cancer.
