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Updated: Nov 11, 2025
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Scaffold-based analysis of nonpeptide oncogenic FTase inhibitors using multiple similarity matching, binding affinity
Qifei Wang1, Fei Chen2, Peng Liu3
1Department of Chest Surgery, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, China.
Abstract:
Oncogenic protein farnesyltransferase (FTase) is a key enzyme responsible for the lipid modification of a large and important number of proteins including Ras, which has been recognized as a druggable target of diverse cancers. Here, we report a systematic scaffold-based analysis to investigate the affinity, selectivity and cross-reactivity of nonpeptide inhibitors across ontology-enriched, disease-associated FTase mutants, by integrating multiple similarity matching, binding affinity scoring and enzyme inhibition assay. It is revealed that nonpeptide inhibitors are generally insensitive to FTase mutations; many of them cannot definitely select for wild-type target over mutant enzymes. Therefore, off-target is observed as a common phenomenon for the untargeted consequence of targeted therapies with FTase inhibition. This is not unexpected if considering that the enzyme active site is highly conserved in composition, configuration and function. The off-target, on the one hand, causes nonpeptide inhibitors with adverse drug reactions and, on the other hand, makes the inhibitors as promising candidates for the new use of old drugs. To practice the latter, a number of unexpected mutant-inhibitor interactions involved in cancer signaling pathways are uncovered in the created profile, from which several nonpeptide inhibitors are identified as insensitive to a drug-resistant mutation. Structural analysis suggests that the inhibitor ligands can bind to the mutant active site in a similar manner with wild-type target, although their nonbonded interactions appear to be impaired moderately upon the mutation.
Insights
Nonpeptide inhibitors targeting farnesyltransferase (FTase) show limited selectivity against FTase mutants, leading to off-target effects. However, some inhibitors remain effective against drug-resistant mutations, suggesting potential for repurposing in cancer therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Biology
Background:
- Oncogenic protein farnesyltransferase (FTase) is crucial for lipid modification of proteins like Ras, a key target in cancer.
- Nonpeptide inhibitors are being developed to target FTase, but their efficacy against cancer-associated mutants is not well understood.
Purpose of the Study:
- To systematically analyze the affinity, selectivity, and cross-reactivity of nonpeptide FTase inhibitors against wild-type and mutant FTase enzymes.
- To investigate the potential for off-target effects and identify inhibitors effective against drug-resistant FTase mutations.
Main Methods:
- Scaffold-based analysis integrating similarity matching, binding affinity scoring, and enzyme inhibition assays.
- Evaluation of nonpeptide inhibitors against a panel of ontology-enriched, disease-associated FTase mutants.
Main Results:
- Nonpeptide FTase inhibitors generally exhibit insensitivity to FTase mutations, often failing to selectively inhibit wild-type over mutant enzymes.
- Off-target effects are common due to the conserved nature of the FTase active site, potentially causing adverse drug reactions.
- Several nonpeptide inhibitors demonstrated efficacy against drug-resistant FTase mutations, with structural analysis indicating similar binding modes to the mutant active site.
Conclusions:
- The conserved active site of FTase contributes to the limited selectivity of nonpeptide inhibitors against mutants.
- Off-target interactions present challenges for targeted therapy but also highlight opportunities for drug repurposing.
- Identified inhibitors effective against drug-resistant mutants offer potential for novel therapeutic strategies in cancer treatment.
