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Updated: Aug 10, 2025
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Synthesis, kinetics and cellular studies of new phenothiazine analogs as potent human-TLK inhibitors
Delna Johnson1, Javeena Hussain1, Siddhant Bhoir2
1Discipline of Chemistry, Indian Institute of Technology, Gandhinagar, Gujarat, 382355, India. priyak@iitgn.ac.in.
Abstract:
The alterations in the expression patterns of protein kinases often implicate human cancer initiation and progression. Human tousled-like kinases (TLKs), both TLK1/1B and TLK2, are evolutionary kinases found in cell signaling pathways and are involved in DNA repair, replication, and chromosomal integrity. Several reports have demonstrated the numerous roles of TLK1B in the development and progression of cancer via its interactions with different partners, and this direct association has made them viable molecular targets for cancer therapy. Previous studies have shown phenothiazines to be potent TLK1B inhibitors. Herein, we report the design and synthesis of a class of phenothiazine molecules and their biological inhibitory effect on hTLK1B/KD through in vitro kinase assays, cellular assays, and in silico studies. We identified a few inhibitors with better inhibition and physio-chemical properties than the reported TLK1B inhibitors using a recombinant human tousled-like kinase 1B-kinase domain (hTLK1B-KD). Very interestingly, inhibitory activity with LNCap cells was found to be on the sub-nanomolar level. Our attempts to study the newly designed phenothiazine analogs, as well as generate a stable catalytically active hTLK1B-KD in high yield, represent a fundamental step towards the structure-based design of future TLK-specific inhibitors.
Insights
Researchers designed novel phenothiazine molecules as potent inhibitors of human tousled-like kinase 1B (hTLK1B). These compounds show significant promise for cancer therapy by targeting key cellular processes involved in tumor growth.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Protein kinase alterations are implicated in cancer initiation and progression.
- Human tousled-like kinases (TLKs) regulate DNA repair, replication, and chromosomal integrity.
- TLK1B plays a significant role in cancer development and is a potential therapeutic target.
Purpose of the Study:
- To design and synthesize novel phenothiazine derivatives as inhibitors of human TLK1B.
- To evaluate the biological inhibitory effects of these compounds on hTLK1B kinase activity.
- To identify potent TLK1B inhibitors with improved properties for cancer therapy.
Main Methods:
- Synthesis of a new class of phenothiazine molecules.
- In vitro kinase assays using recombinant human TLK1B-kinase domain (hTLK1B-KD).
- Cellular assays using LNCap cells and in silico studies.
Main Results:
- Identified several phenothiazine inhibitors with superior inhibition and physicochemical properties compared to existing TLK1B inhibitors.
- Achieved sub-nanomolar inhibitory activity against hTLK1B in LNCap cells.
- Successfully generated a stable, catalytically active hTLK1B-KD for further studies.
Conclusions:
- The newly designed phenothiazine analogs are potent inhibitors of hTLK1B.
- These findings represent a crucial advancement in developing structure-based TLK-specific inhibitors for cancer treatment.
- The identified compounds hold promise for future cancer therapeutic strategies targeting TLK1B.
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