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Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of
Mikhail Krasavin1, Stanislav Kalinin1, Tatiana Sharonova1
1Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia.
Abstract:
Analysis of the literature data reveals that while inhibition of cancer-related carbonic anhydrase IX and XII isoforms continues to be an important enrichment factor for designing anticancer agent development libraries, exclusive reliance on the in vitro inhibition of these two recombinant isozymes in nominating candidate compounds for evaluation of their effects on cancer cells may lead not only to identifying numerous compounds devoid of the desired cellular efficacy but also to overlooking many promising candidates which may not display the best potency in biochemical inhibition assay. However, SLC-0111, now in phase Ib/II clinical trials, was developed based on the excellent agreement between the in vitro, in vivo and more recently, in-patient data.
Insights
Targeting cancer-related carbonic anhydrase IX and XII is crucial for anticancer drug development. Relying solely on in vitro assays may miss effective compounds; a holistic approach ensures better candidate selection.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Cancer-associated carbonic anhydrase IX and XII are key targets for anticancer drug discovery.
- In vitro inhibition assays are commonly used to screen potential anticancer agents.
- Over-reliance on in vitro data can lead to the selection of ineffective compounds or the exclusion of promising candidates.
Purpose of the Study:
- To evaluate the limitations of using only in vitro carbonic anhydrase inhibition data for anticancer drug development.
- To highlight the importance of integrating in vitro, in vivo, and clinical data for identifying effective anticancer agents.
Main Methods:
- Literature data analysis on carbonic anhydrase inhibitors.
- Review of drug development strategies focusing on cancer-related carbonic anhydrase isoforms.
- Case study of SLC-0111 development.
Main Results:
- Exclusive reliance on in vitro inhibition of carbonic anhydrase IX and XII may result in compounds lacking cellular efficacy.
- Promising drug candidates might be overlooked if they do not show high potency in biochemical assays.
- The drug candidate SLC-0111, currently in clinical trials, demonstrates successful development through integrated in vitro, in vivo, and clinical data.
Conclusions:
- A comprehensive approach combining in vitro, in vivo, and clinical data is essential for successful anticancer drug development.
- The development of SLC-0111 validates the strategy of integrating multiple data types for identifying effective anticancer agents targeting carbonic anhydrases.
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