Alkylation of nucleobases by 2-chloro--diethylethanamine hydrochloride (CDEAH) sensitizes -deficient tumors.

Targeting - and -deficient tumors through synthetic lethality using poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged as a successful strategy for cancer therapy. PARPi monotherapy has shown excellent efficacy and safety profiles in clinical practice but is limited by the need for tumor genome mutations in or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro--diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills - and xeroderma pigmentosum A-deficient cells. CDEAH is a monofunctional alkylating agent that preferentially alkylates guanine nucleobases, forming DNA adducts that can be removed from DNA by either a PARP1-dependent base excision repair or nucleotide excision repair. Treatment of -deficient cells leads to the formation of strand breaks, an accumulation of cells in S phase and activation of the DNA damage response. Furthermore, CDEAH selectively inhibits -deficient xenograft tumor growth compared to isogenic -proficient tumors. Collectively, we report the discovery of an alkylating agent inducing DNA damage that requires PARP1 activity for repair and acts synergistically with PARPi.