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Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic
Ting Wang1,2, Jingyu Wang2, Gongxiong Yao2
11The Third Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract:
PKMYT1 is a validated therapeutic target in pancreatic cancer due to its critical role in controlling the G2/M transition of the cell cycle. In this study, a structure-based drug discovery pipeline was implemented to identify novel PKMYT1 inhibitors with high binding stability and anticancer potential. Pharmacophore models were constructed from four PKMYT1 co-crystal structures, and virtual screening was performed against a large compound library. Through molecular docking and intersection analysis, five consensus high-affinity compounds were identified, among which HIT101481851 demonstrated the most favorable binding characteristics. Molecular dynamics simulations confirmed its stable interactions with key residues such as CYS-190 and PHE-240 across multiple PKMYT1 conformations. ADMET predictions indicated good gastrointestinal absorption, acceptable drug-likeness, and low risk of off-target reactivity. Furthermore, in vivo experiments showed that HIT101481851 inhibited the viability of pancreatic cancer cell lines in a dose-dependent manner while exhibiting lower toxicity toward normal pancreatic epithelial cells. These results suggest that HIT101481851 is a promising lead compound for the development of PKMYT1-targeted therapeutics in pancreatic cancer.
Insights
Researchers identified HIT101481851 as a promising drug candidate targeting PKMYT1 (Protein Kinase Myristoylated 1) for pancreatic cancer treatment. This novel inhibitor shows high binding stability and effectively reduces cancer cell viability with low toxicity.
Area of Science:
- Oncology
- Pharmacology
- Structural Biology
Background:
- PKMYT1 (Protein Kinase Myristoylated 1) is crucial for cell cycle progression and a validated therapeutic target in pancreatic cancer.
- Developing targeted therapies for pancreatic cancer remains a significant challenge due to its aggressive nature and limited treatment options.
Purpose of the Study:
- To identify novel inhibitors of PKMYT1 with high binding stability and potential anticancer activity using a structure-based drug discovery approach.
- To evaluate the efficacy and safety profile of identified lead compounds for pancreatic cancer therapy.
Main Methods:
- Construction of pharmacophore models based on PKMYT1 co-crystal structures.
- Virtual screening of a large compound library, followed by molecular docking and intersection analysis.
- Molecular dynamics simulations and ADMET predictions to assess binding stability and pharmacokinetic properties.
- In vivo evaluation of lead compound efficacy and toxicity in pancreatic cancer models.
Main Results:
- Five high-affinity PKMYT1 inhibitors were identified, with HIT101481851 showing the most favorable binding characteristics.
- HIT101481851 exhibited stable interactions with key PKMYT1 residues (CYS-190, PHE-240) and favorable ADMET predictions.
- In vivo studies demonstrated that HIT101481851 dose-dependently inhibited pancreatic cancer cell viability with reduced toxicity to normal cells.
Conclusions:
- HIT101481851 is a promising lead compound for developing novel PKMYT1-targeted therapeutics for pancreatic cancer.
- The structure-based drug discovery pipeline successfully identified a potent and selective inhibitor with therapeutic potential.
