CLK2 and CLK4 are regulators of DNA damage-induced NF-κB targeted by novel small molecule inhibitors.
Cell Chem Biol
; 30(10): 1303-1312.e3, 2023 10 19.
Article
en En
| MEDLINE
| ID: mdl-37506701
ABSTRACT
Transcription factor NF-κB potently activates anti-apoptotic genes, and its inactivation significantly reduces tumor cell survival following genotoxic stresses. We identified two structurally distinct lead compounds that selectively inhibit NF-κB activation by DNA double-strand breaks, but not by other stimuli, such as TNFα. Our compounds do not directly inhibit previously identified regulators of this pathway, most critically including IκB kinase (IKK), but inhibit signal transmission in-between ATM, PARP1, and IKKγ. Deconvolution strategies, including derivatization and in vitro testing in multi-kinase panels, yielded shared targets, cdc-like kinase (CLK) 2 and 4, as essential regulators of DNA damage-induced IKK and NF-κB activity. Both leads sensitize to DNA damaging agents by increasing p53-induced apoptosis, thereby reducing cancer cell viability. We propose that our lead compounds and derivatives can be used in context of genotoxic therapy-induced or ongoing DNA damage to increase tumor cell apoptosis, which may be beneficial in cancer treatment.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
FN-kappa B
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cell Chem Biol
Año:
2023
Tipo del documento:
Article
País de afiliación:
Alemania