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Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors

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Title
Alkylation of nucleobases by 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) sensitizes PARP1-deficient tumors
Author(s)
Minwoo Wie; Keon Woo Khim; Arnold S Groehler Iv; Soomin Heo; Woo, Junhyeok; Kook Son; Eun A Lee; Jae Sun Ra; Hong, Sung You; Orlando D Schärer; Jang Hyun Choi; Kyungjae Myung
Publication Date
2023-09
Journal
NAR Cancer, v.5, no.3
Publisher
Oxford University Press
Abstract
Targeting BRCA1-and BRCA2-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 BRCA or other homologous recombination genes as well as the rapid emergence of resistance. In this study, we identified 2-chloro-N,N-diethylethanamine hydrochloride (CDEAH) as a small molecule that selectively kills PARP1-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 PARP1-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 PARP1-deficient xenograft tumor growth compared to isogenic PARP1-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. © 2023 The Author(s). Published by Oxford University Press on behalf of NAR Cancer.
URI
https://pr.ibs.re.kr/handle/8788114/14431
DOI
10.1093/narcan/zcad042
ISSN
2632-8674
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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