TLK1

Last update 08 May 2025

Basic Info

Synonyms

KIAA0137, PKU-beta, Serine/threonine-protein kinase tousled-like 1

+ [3]

Introduction

Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase. This is cell cycle checkpoint and ATM-pathway dependent and appears to regulate processes involved in chromatin assembly. Isoform 3 phosphorylates and enhances the stability of the t-SNARE SNAP23, augmenting its assembly with syntaxin. Isoform 3 protects the cells from the ionizing radiation by facilitating the repair of DSBs. In vitro, phosphorylates histone H3 at 'Ser-10'.

100 Clinical Results associated with TLK1

100 Translational Medicine associated with TLK1

0 Patents (Medical) associated with TLK1

Literatures (Medical) associated with TLK1

01 May 2025·Bioorganic Chemistry

Characterization of new non-ATP dependent inhibitors of TLK1 as potential molecules for treating prostate cancer

Article

Author: Thiruvenkatam, Vijay ; Sharma, Shivangi ; Kirubakaran, Sivapriya ; Johnson, Delna

Androgen deprivation therapy (ADT) is currently the primary treatment regime for Prostate cancer patients for advanced and local tumors. However, 70 % of the patients develop resistance to ADT due to various underlying mechanisms over the years. Researchers have identified the involvement of Tousled-like kinase 1 (TLK1) as a primary reason for ADT resistance and metastatic tumor development, representing TLK1 as an effective druggable target for prostate cancer. To date, phenothiazines-which are known antipsychotic drugs, are the only class of inhibitors reported against TLK1. In this study, we focus on developing a new class of TLK1 inhibitors to broaden the spectrum of understanding TLK1 inhibition. As an approach, we designed, synthesized, and validated pyridazinone-fused indole molecules with potent TLK1 inhibition with the concept of ligand-based drug discovery. The inhibition studies and biochemical assays identified a molecule 5n with better inhibition potential than reported J54. Also, the synthesized inhibitors are toxic to androgen-sensitive LNCaP prostate cancer cell lines in sub-micromolar levels and inhibit the TLK1 pathway in cells. Additionally, the combination of anti-androgens and 5n reduces the clonogenicity of cells, causes an accumulation of DNA damage, and induces apoptosis cell death in the LNCaP cells. We anticipate that our step towards exploring a new class of potent TLK1 inhibitors would aid in elevating the therapeutics to existing prostate cancer therapy and provide strong validation for future drug design for more potent and specific TLK1 inhibitors.

08 Feb 2025·Nucleic Acids Research

Autophosphorylation of the Tousled-like kinases TLK1 and TLK2 regulates recruitment to damaged chromatin via PCNA interaction

Article

Author: Raney, Kevin D ; Leung, Justin W ; Tengler, Kyle A ; West, Kirk L ; Kreiling, Natasha ; Ghosal, Gargi ; Nguyen, Tram T N

AbstractTousled-like kinases 1 and 2 (TLK1 and 2) are cell cycle-regulated serine/threonine kinases that are involved in multiple biological processes. Mutation of TLK1 and 2 confer neurodegenerative diseases. Recent studies demonstrate that TLK1 and 2 are involved in DNA repair. However, there is no direct evidence that TLK1 and 2 function at DNA damage sites. Here, we show that both TLK1 and TLK2 are hyper-autophosphorylated at their N-termini, at least in part, mediated by their homo- or hetero- dimerization. We found that TLK1 and 2 hyper-autophosphorylation suppresses their recruitment to damaged chromatin. Furthermore, both TLK1 and 2 associate with PCNA specifically through their evolutionarily conserved non-canonical PCNA-interacting protein (PIP) box at the N-terminus, and mutation of the PIP-box abolishes their recruitment to DNA damage sites. Mechanistically, the TLK1 and 2 hyper-autophosphorylation masks the PIP-box and negatively regulates their recruitment to the DNA damage site. Overall, our study dissects the detailed genetic regulation of TLK1 and 2 at damaged chromatin, which provides important insights into their emerging roles in DNA repair.

01 Oct 2024·Bioorganic Chemistry

A novel approach to investigate the combinatorial effects of TLK1 (Tousled-Like Kinase1) inhibitors with Temozolomide for glioblastoma therapy

Article

Author: Kirubakaran, Sivapriya ; Chhabria, Dimple ; Priya, Bhanu ; Mahesh Dhongdi, Janhvi

Glioblastoma multiforme (GBM) is an aggressive, incurable brain tumor with poor prognosis and limited treatment options. Temozolomide (TMZ) is the standard chemotherapeutic treatment for GBM, but its efficacy has drawn strong criticism from clinicians due to short survival gains and frequent relapses. One critical limitation of TMZ therapy is the hyperactivation of DNA repair pathways, which over time neutralizes the cytotoxic effects of TMZ, thus highlighting the urgent need for new treatment approaches. Addressing this, our study explores the therapeutic potential of in-house-designed phenothiazine-based Tousled-like kinase-1 (TLK1) inhibitors for GBM treatment. TLK1, overexpressed in GBM, plays a role in DNA repair. Phenothiazines are known to cross the blood-brain barrier (BBB). Among all molecules, J54 was identified as a potential lead molecule with improved cytotoxicity. In the context of O6-methylguanine-DNA methyltransferase (MGMT)-deficient GBM cells, the combined administration of phenothiazines and TMZ exhibited a collective reduction in clonogenic growth, coupled with anti-migratory and anti-invasion effects. Conversely, in MGMT-proficient cells, phenothiazine monotherapy alone showed reduced clonogenic growth, along with anti-migratory and anti-invasion effects. Notably, a synergistic increase in γH2AX levels and concurrent attenuation of DNA repair upon combinatorial exposure to TMZ and J54 were observed, implying increased cytotoxicity due to sustained DNA strand breaks. Overall, this study provides new insights into TLK1 inhibition for GBM therapy. Collectively, these findings indicate that TLK1 is one of the upregulated kinases in GBM and phenothiazine-based TLK1 inhibitors could be a promising treatment option for GBM patients.

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TLK1

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