Novel allosteric PARP1 inhibitors for the treatment of BRCA-deficient leukemia.

ABSTRACT: The successful use of PARP1 inhibitors like olaparib (Loparza^®) in the treatment of BRCA1/2- deficient breast cancer has provided clinical proof of concept for applying personalized medicine based on synthetic lethality to the treatment of cancer. Unfortunately, all marketed PARP1 inhibitors act by competing with the cofactor NAD⁺ and resistance is already developing to this anti-cancer mechanism. Allosteric PARP1 inhibitors could provide a means of overcoming this resistance. A high throughput screen performed by Tulin et al. identified 5F02 as an allosteric PARP inhibitor that acts by preventing the enzymatic activation of PARP1 by histone H4. 5F02 demonstrated anti-cancer activity in several cancer cell lines and was more potent than olaparib and synergistic with o

SUBMITTER: Hewlett E 

PROVIDER: S-EPMC7560981 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature