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Published on: August 5, 2022
Identification of medicinal compounds as potential inhibitors for mutated isocitrate dehydrogenases against
Fahad Hassan Shah1, Song Ja Kim1
1Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 32588, Republic of Korea.
Abstract:
Chondrosarcoma is the third most common cartilaginous bone tumour that is insusceptible to radio- and chemotherapy and it is inclined to metastasis. These resistant qualities are facilitated by mutant variants of isocitrate dehydrogenases (IDH) 1-2 enzyme. These mutant enzymes promote oncogenesis of chondrocytes by changing their epigenetic wardrobe leading to tumour formation. Presently, there are lack of drugs available to be exploited as a remedy for this disease. On the other hand, majority of chemotherapeutic drugs induce cytotoxicity in the cancer cells at the cost of harming surrounding healthy cells, jeopardizing human life. The current study is focused on screening various medicinal compounds against IDH1 and IDH2 combined with insilico gene expression, cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) studies to elucidate the molecular mechanism against chondrosarcoma and also to uncover pharmacokinetic profile of these compounds. Screening of 5000+ compounds filtered two efficacious compounds (Artocarpetin and 5-Galloylquinic acid) capable of establishing hydrogen bond connections with both IDH variants. Other studies showed that these compounds downregulate ITGAV, CARPIN1, CCL5 and COG5 and TNFRSF10B gene that reduces chondrogenesis and inflammation, Artocarpetin and 5-galloylquinic acid are TP53 expression enhancer and inhibit MM9 expression that promote immunomodulation and apoptosis in these cancers. These compounds are both active against CHSA8926 and CHSA011 cell line of chondrosarcoma. However, the ADME profile of 5-galloylquinic acid is slightly unsatisfactory based on druglikness and bioavailability score criteria as compared to artocarpetin. Both of these compounds are class-5 chemicals and require high doses to elicit adverse response. Our results suggest that artocarpetin and 5-galloylquinic acid are efficacious drug candidates and could be further exploited to validate these findings in vitro.
Insights
Researchers identified two potential chondrosarcoma drugs, Artocarpetin and 5-Galloylquinic acid, targeting IDH1 and IDH2 enzymes. These compounds show promise in reducing tumor growth and promoting apoptosis, offering new therapeutic avenues for this resistant bone cancer.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Chondrosarcoma, a common bone tumor, is resistant to conventional therapies and prone to metastasis.
- Mutant isocitrate dehydrogenases (IDH) 1-2 enzymes drive oncogenesis by altering chondrocyte epigenetics.
- Limited effective treatments exist, and current chemotherapy often harms healthy cells.
Purpose of the Study:
- To screen medicinal compounds for activity against IDH1 and IDH2 variants in chondrosarcoma.
- To elucidate the molecular mechanisms of potential chondrosarcoma drugs.
- To evaluate the pharmacokinetic profiles, including ADMET properties, of promising compounds.
Main Methods:
- Screening of over 5000 compounds against IDH1 and IDH2.
- In silico gene expression analysis, cytotoxicity assays, and ADMET studies.
- Evaluation of drug-target interactions, gene regulation, and cell line activity.
Main Results:
- Artocarpetin and 5-Galloylquinic acid were identified as effective inhibitors targeting both IDH1 and IDH2.
- These compounds downregulate genes involved in chondrogenesis and inflammation (e.g., ITGAV, CARPIN1) and enhance TP53 expression.
- Both compounds demonstrated activity against chondrosarcoma cell lines (CHSA8926, CHSA011), with Artocarpetin showing a superior ADME profile.
Conclusions:
- Artocarpetin and 5-Galloylquinic acid are promising drug candidates for chondrosarcoma treatment.
- Their mechanisms involve modulating gene expression, promoting immunomodulation, and inducing apoptosis.
- Further in vitro validation is recommended to explore their therapeutic potential.
