Design and Synthesis of Aminopyrimidinyl Pyrazole Analogs as PLK1 Inhibitors Using Hybrid 3D-QSAR and Molecular
Swapnil P Bhujbal1,2, Hyejin Kim1,2, Hyunah Bae1,2
1Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 426-791, Korea.
Abstract:
Cancer continues to be one of the world's most severe public health issues. Polo-like kinase 1 (PLK1) is one of the most studied members of the polo-like kinase subfamily of serine/threonine protein kinases. PLK1 is a key mitotic regulator responsible for cell cycle processes, such as mitosis initiation, bipolar mitotic spindle formation, centrosome maturation, the metaphase to anaphase transition, and mitotic exit, whose overexpression is often associated with oncogenesis. Moreover, it is also involved in DNA damage response, autophagy, cytokine signaling, and apoptosis. Due to its fundamental role in cell cycle regulation, PLK1 has been linked to various types of cancer onset and progression, such as lung, colon, prostate, ovary, breast cancer, melanoma, and AML. Hence, PLK1 is recognized as a critical therapeutic target in the treatment of various proliferative diseases. PLK1 inhibitors developed in recent years have been researched and studied through clinical trials; however, most of them have failed because of their toxicity and poor therapeutic response. To design more potent and selective PLK1 inhibitors, we performed a receptor-based hybrid 3D-QSAR study of two datasets, possessing similar common scaffolds. The developed hybrid CoMFA (q = 0.628, r = 0.905) and CoMSIA (q = 0.580, r = 0.895) models showed admissible statistical results. Comprehensive, molecular docking of one of the most active compounds from the dataset and hybrid 3D-QSAR studies revealed important active site residues of PLK1 and requisite structural characteristics of ligand to design potent PLK1 inhibitors. Based on this information, we have proposed approximately 38 PLK1 inhibitors. The newly designed PLK1 inhibitors showed higher activity (predicted pIC50) than the most active compounds of all the derivatives selected for this study. We selected and synthesized two compounds, which were ultimately found to possess good IC50 values. Our design strategy provides insight into development of potent and selective PLK1 inhibitors.
Insights
This study developed novel Polo-like kinase 1 (PLK1) inhibitors for cancer treatment. New inhibitors show improved potency and selectivity, offering a promising therapeutic strategy.
Area of Science:
- Biochemistry and Molecular Biology
- Medicinal Chemistry
- Oncology
Background:
- Polo-like kinase 1 (PLK1) is a crucial mitotic regulator overexpressed in various cancers, making it a key therapeutic target.
- Existing PLK1 inhibitors have faced challenges with toxicity and limited efficacy in clinical trials.
- Developing potent and selective PLK1 inhibitors is essential for effective cancer therapy.
Purpose of the Study:
- To design novel, potent, and selective Polo-like kinase 1 (PLK1) inhibitors.
- To identify key structural features and active site residues of PLK1 for inhibitor design.
- To provide a rational drug design strategy for future PLK1-targeted cancer therapies.
Main Methods:
- Utilized a receptor-based hybrid 3D-Quantitative Structure-Activity Relationship (3D-QSAR) study on two datasets with common scaffolds.
- Employed molecular docking to analyze interactions between ligands and PLK1 active site residues.
- Designed and synthesized new PLK1 inhibitors based on computational modeling and QSAR predictions.
Main Results:
- Developed statistically significant hybrid CoMFA and CoMSIA models (q values > 0.58, r values > 0.89).
- Identified critical PLK1 active site residues and essential ligand structural characteristics for potent inhibition.
- Designed 38 novel PLK1 inhibitors with predicted higher activity than existing compounds; two synthesized compounds demonstrated good IC50 values.
Conclusions:
- The hybrid 3D-QSAR and molecular docking approach successfully guided the design of potent and selective PLK1 inhibitors.
- The developed inhibitors show promise for overcoming the limitations of previous PLK1-targeted therapies.
- This strategy offers valuable insights for the rational development of next-generation anti-cancer agents targeting PLK1.
