YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors Article Swipe
Yuting Sun
,
Hui Yang
,
Jiaqi Yuan
,
Li‐Min Wang
,
Shanshan Song
,
Rongrong Chen
,
Xubin Bao
,
Jia Li
,
Tiantian Yang
,
Xiaofei Zhang
,
Qian He
,
Yong Gan
,
Ze‐Hong Miao
,
Jin‐Xue He
,
Chunhao Yang
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.3c00821
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.3c00821
Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure-activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1021/acs.jmedchem.3c00821
- OA Status
- green
- Cited By
- 12
- References
- 53
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4386046294
All OpenAlex metadata
Raw OpenAlex JSON
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https://openalex.org/W4386046294Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1021/acs.jmedchem.3c00821Digital Object Identifier
- Title
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YCH1899, a Highly Effective Phthalazin-1(2H)-one Derivative That Overcomes Resistance to Prior PARP InhibitorsWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-08-22Full publication date if available
- Authors
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Yuting Sun, Hui Yang, Jiaqi Yuan, Li‐Min Wang, Shanshan Song, Rongrong Chen, Xubin Bao, Jia Li, Tiantian Yang, Xiaofei Zhang, Qian He, Yong Gan, Ze‐Hong Miao, Jin‐Xue He, Chunhao YangList of authors in order
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https://doi.org/10.1021/acs.jmedchem.3c00821Publisher landing page
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://doi.org/10.7270/q2zs31zbDirect OA link when available
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Chemistry, Derivative (finance), Stereochemistry, Pharmacology, Business, Medicine, FinanceTop concepts (fields/topics) attached by OpenAlex
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12Total citation count in OpenAlex
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2025: 7, 2024: 4, 2023: 1Per-year citation counts (last 5 years)
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10Other works algorithmically related by OpenAlex
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