CLK2 (CDC Like Kinase 2)

Pharmacologically, dedicated inhibitors like Infigratinib have demonstrated anti-tumor activity in clinical Phase II trials for FGFR-altered recurrent gliomas, while the multi-kinase inhibitor Regorafenib has shown a modest survival benefit in recurrent GBM; however, mechanistic studies indicate that effective response often relies on co-targeting bypass pathways (e.g., CLK2) and mitigating the tumor's metabolic dependency. Crucially, limited drug exposure through the blood-brain barrier (BBB) continues to be the foremost challenge, dictating optimization efforts toward compounds with favorable pharmacokinetic properties and novel delivery platforms, such as the covalent inhibitor futibatinib and liposomal formulations, to enhance brain penetrance. In conclusion, the evolving molecular landscape validates FGFR alterations as a targetable niche in gliomas, and future success depends critically on integrating comprehensive next-generation sequencing to identify aggressive FGFR variants, developing next-generation inhibitors with superior BBB permeability, and implementing rational combination strategies to achieve durable clinical benefit.

Based on this observation, we have been able to transform a molecule (DB18) previously established with a very low activity on CLK3 into a derivative VS-77 which has now a significant affinity toward CLK3 (IC50 = 0.3 μM). Thus, VS-77 appears as a new pan-inhibitor of the CLK family.

Furthermore, combining the ferroptosis inducer Erastin with Oxaliplatin significantly enhanced anti-tumor efficacy in CLK2-deficient xenograft models. Together, this study establishes CLK2 as a critical inhibitor of ferroptosis via the KEAP1/NRF2/HMOX1 and p53/SLC7A11 axes, supporting its potential as a therapeutic target for CRC.

Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of 7c. The good in vitro activity and promising pharmacokinetic properties indicated that the 7c was a reliable lead compound for further development.

Targeting CLK2 shows antitumor effects on MM partially through inhibiting SRSF phosphorylation and inducing NMD of RAE1. Therefore, targeting the CLK2/SRSFs/RAE1 axis could be a potential therapeutic strategy for MM.

Additionally, significant antiproliferative activity was observed for LBM22 in 3D cultured H1975OR cells. In conclusion, LBM22 emerges as a promising CLK2 inhibitor for the treatment of NSCLC.

The application of itaconate demonstrates efficacy in inhibiting RB cell proliferation, validated through in vitro and in vivo models. This study emphasizes ALDOA as a promising target for innovative RB therapies, with potential implications for altering tumor energy metabolism.

Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

Notably, expressing the CLK2 condensates hampers the maintenance of GSCs. In conclusion, this research unveils a mechanism by which IR is propelled by CLK2 condensates, shedding light on its role in coping with cellular stress.

Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

Moreover, AANL-SeNPs could inhibit the cell proliferation and migration, and enhance the sensitivity of lung cancer cells to osimertinib and has no toxic to normal cells...A significantly upregulated protein, CDC-like kinase 2 (CLK2), was screened and validated for further analysis, which showed that the expression levels of CLK2 were increased in H157 and H1437 cells after AANL-SeNPs treatment. The results obtained in this study suggest that a novel selenium nanocomposite AANL-SeNPs, which inhibits lung cancer by upregulating the expression of CLK2.