Related Experiment Video
Updated: Aug 14, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Discovery of potent and noncovalent KRASG12D inhibitors: Structure-based virtual screening and biological evaluation
Yuting Wang1, Hai Zhang2, Jindong Li3
1Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Abstract:
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of pancreatic cancer. Herein, we identified four potent and noncovalent KRASG12D inhibitors (hits 1-4) by using structure-based virtual screening and biological evaluation. The in vitro assays indicated that the four compounds had sub-nanomolar affinities for KRASG12D and showed a dose-dependent inhibitory effect on human pancreatic cancer cells. In particular, the hit compound 3 was the most promising candidate and significantly inhibited the tumor growth of pancreatic cancer in tumor-bearing mice. The hit compound 3 represented a promising starting point for structural optimization in hit-to-lead development. This study shows that hit compound 3 provides a basis for the development of the treatment of cancer driven by KRASG12D.
Insights
Researchers identified four novel KRASG12D inhibitors for pancreatic cancer treatment. Hit compound 3 showed significant anti-tumor effects in preclinical models, offering a promising foundation for new cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Drug Discovery
Background:
- KRASG12D mutations are prevalent in pancreatic cancer, driving tumor growth.
- Targeting KRASG12D represents a significant therapeutic opportunity for pancreatic ductal adenocarcinoma.
- Developing effective KRASG12D inhibitors is crucial for advancing pancreatic cancer treatment.
Purpose of the Study:
- To identify novel, noncovalent inhibitors targeting the KRASG12D mutation.
- To evaluate the potency and efficacy of identified inhibitors against pancreatic cancer.
- To establish a lead compound for further drug development against KRASG12D-driven cancers.
Main Methods:
- Structure-based virtual screening was employed to identify potential KRASG12D inhibitors.
- In vitro biological assays were conducted to assess compound affinity and cellular activity.
- In vivo studies in tumor-bearing mice evaluated the anti-tumor efficacy of lead compounds.
Main Results:
- Four potent, noncovalent KRASG12D inhibitors (hits 1-4) were identified.
- Compounds demonstrated sub-nanomolar affinities for KRASG12D and dose-dependent inhibition of pancreatic cancer cells.
- Hit compound 3 exhibited significant inhibition of tumor growth in preclinical mouse models.
Conclusions:
- Hit compound 3 is a promising candidate for further development as a KRASG12D inhibitor.
- This study provides a strong foundation for developing new treatments for KRASG12D-driven pancreatic cancer.
- The identified compounds represent valuable starting points for hit-to-lead optimization in oncology drug discovery.
