Reinvent Aliphatic Arsenicals as Reversible Covalent Warheads toward Targeted Kinase Inhibition and Non-acute Promyelocytic Leukemia Cancer Treatment.
J Med Chem
; 67(7): 5458-5472, 2024 Apr 11.
Article
en En
| MEDLINE
| ID: mdl-38556750
ABSTRACT
The success of arsenic in acute promyelocytic leukemia (APL) treatment is hardly transferred to non-APL cancers, mainly due to the low selectivity and weak binding affinity of traditional arsenicals to oncoproteins critical for cancer survival. We present herein the reinvention of aliphatic trivalent arsenicals (As) as reversible covalent warheads of As-based targeting inhibitors toward Bruton's tyrosine kinase (BTK). The effects of As warheads' valency, thiol protection, methylation, spacer length, and size on inhibitors' activity were studied. We found that, in contrast to the bulky and rigid aromatic As warhead, the flexible aliphatic As warheads were well compatible with the well-optimized guiding group to achieve nanomolar inhibition against BTK. The optimized As inhibitors effectively blocked the BTK-mediated oncogenic signaling pathway, leading to elevated antiproliferative activities toward lymphoma cells and xenograft tumor. Our study provides a promising strategy enabling rational design of new aliphatic arsenic-based reversible covalent inhibitors toward non-APL cancer treatment.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Arsénico
/
Arsenicales
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Leucemia Promielocítica Aguda
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China