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Updated: Jan 2, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual
E M Mamontova1, A L Zakharenko2, O D Zakharova2
1Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk 630090, Russian Federation; Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation.
Abstract:
Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme. The crucial His493 in TDP1's binding site is replaced with an arginine amino acid residue rendering the enzyme dysfunctional. A virtual screen was performed against the homology model of SCAN1 and seventeen compounds were identified and tested in a novel SCAN1 specific biochemical assay. Six compounds showed activity with IC50 values between 3.5 and 25.1 µM. The most active ligand 5 (3.5 µM) is a dicoumarin followed by a close structural analogue 6 at 6.0 µM. A less potent series of β-carbolines (14 and 15) was found with potency in the mid-teens. According to molecular modelling an excellent fit for the active ligands into the binding pocket is predicted. To the best of our knowledge, data on inhibitors of the mutant form of TDP1 has not been reported previously. The virtual hits were also tested for wild type TDP1 activity and all six SCAN1 inhibitors are potent for the former, e.g., ligand 5 has a measured IC50 at 99 nM. In the last decade, TDP1 is considered as a promising target for adjuvant therapy against cancer in combination with Topoisomerase 1 poisons. The active ligands are mostly non-toxic to cancer cell lines A-549, T98G and MCF-7 as well as the immortalized WI-38 human fetal lung cells. Furthermore, ligands 5 and 7, show promising synergy in conjunction with topotecan, a clinically used topoisomerase 1 anticancer drug. The active ligands 5, 7, 14 and 15 have a good balance of the physicochemical properties required for oral bioavailability making the excellent candidates for further development.
Insights
Researchers identified novel inhibitors for the mutant Tyrosyl-DNA phosphodiesterase 1 (TDP1) enzyme, crucial for treating Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). These compounds show potential for cancer therapy and oral drug development.
Area of Science:
- Biochemistry
- Neuroscience
- Drug Discovery
Background:
- Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a neurological disorder caused by a mutation in the Tyrosyl-DNA phosphodiesterase 1 (TDP1) enzyme.
- The His493 mutation in TDP1 renders the DNA repair enzyme dysfunctional, leading to disease pathology.
Purpose of the Study:
- To identify novel small molecule inhibitors targeting the mutant TDP1 enzyme associated with SCAN1.
- To evaluate the potential of these inhibitors as therapeutic agents for SCAN1 and as adjuncts in cancer therapy.
Main Methods:
- A virtual screening was conducted against a homology model of the SCAN1-mutant TDP1 enzyme.
- Seventeen compounds were identified and tested in a SCAN1-specific biochemical assay.
- Inhibitor activity was assessed using IC50 values, and molecular modeling was employed to predict ligand binding.
Main Results:
- Six compounds demonstrated inhibitory activity against mutant TDP1, with IC50 values ranging from 3.5 to 25.1 µM.
- The most potent inhibitors were a dicoumarin (ligand 5, IC50 = 3.5 µM) and a structural analogue (ligand 6, IC50 = 6.0 µM).
- All identified inhibitors also showed potency against wild-type TDP1, with ligand 5 exhibiting an IC50 of 99 nM.
Conclusions:
- Novel inhibitors of mutant TDP1 have been identified, representing a potential therapeutic strategy for SCAN1.
- The active ligands are non-toxic to various cancer cell lines and normal cells, and show synergy with the anticancer drug topotecan.
- Selected ligands possess favorable physicochemical properties for oral bioavailability, indicating their potential for further drug development.
