Recent Discovery of PARP7 Inhibitors as Anticancer Agents

Kargbo, Robert B.

doi:10.1021/acsmedchemlett.2c00416

Cited by 3 publications

(4 citation statements)

References 6 publications

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“…Radioactive iodine is first-line for metastatic papillary thyroid cancer, but 60% develop resistance necessitating new strategies [ 48 ]. In some models, TIPARP inhibitors show persistent tumor growth suppression, potent antiproliferative effects, and restored interferon signaling [ 49 ]. Our CellMiner analysis revealed correlations between TIPARP and drug sensitivities like Homoharringtonine and Fluvastatin.…”

Section: Discussionmentioning

confidence: 99%

TIPARP as a prognostic biomarker and potential immunotherapeutic target in male papillary thyroid carcinoma

Zhang,

Zhou,

Yao

et al. 2024

Cancer Cell Int

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Background Male patients with papillary thyroid carcinoma (PTC) tend to have poorer prognosis compared to females, partially attributable to a higher rate of lymph node metastasis (LNM). Developing a precise predictive model for LNM occurrence in male PTC patients is imperative. While preliminary predictive models exist, there is room to improve accuracy. Further research is needed to create optimized prognostic models specific to LNM prediction in male PTC cases. Methods We conducted a comprehensive search of publicly available microarray datasets to identify candidate genes continuously upregulated or downregulated during PTC progression in male patients only. Univariate Cox analysis and lasso regression were utilized to construct an 11-gene signature predictive of LNM. TIPARP emerged as a key candidate gene, which we validated at the protein level using immunohistochemical staining. A prognostic nomogram incorporating the signature and clinical factors was developed based on the TCGA cohort. Results The 11-gene signature demonstrated good discriminative performance for LNM prediction in training and validation datasets. High TIPARP expression associated with advanced stage, high T stage, and presence of LNM. A prognostic nomogram integrating the signature and clinical variables reliably stratified male PTC patients into high and low recurrence risk groups. Conclusions We identified a robust 11-gene signature and prognostic nomogram for predicting LNM occurrence in male PTC patients. We propose TIPARP as a potential contributor to inferior outcomes in males, warranting further exploration as a prognostic biomarker and immunotherapeutic target. Our study provides insights into the molecular basis for gender disparities in PTC.

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Section: Discussionmentioning

confidence: 99%

TIPARP as a prognostic biomarker and potential immunotherapeutic target in male papillary thyroid carcinoma

Zhang,

Zhou,

Yao

et al. 2024

Cancer Cell Int

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“…The assay was mentioned as previously reported, including ARTD family subtypes Take the determination method of compounds’ inhibitory activities on PARP1 as an example. In short, a 96-well plate was incubated with 20 μg/mL histone and blocked with 1% (w/v) BSA overnight.…”

Section: Methodsmentioning

confidence: 99%

“…β-Actin was used to normalize the level of mRNA expression. The primers of targets were mentioned in the previously published article …”

Section: Methodsmentioning

confidence: 99%

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Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy

Gu,

Yan,

Yang

et al. 2023

J. Med. Chem.

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PARP7 plays a crucial role in cancer immunity. The inhibition of PARP7 has shown potential in boosting the immune response against cancer, making it an attractive target for cancer immunotherapy. Herein, we employed a rigid constraint strategy (reduction in molecular flexibility) to design and synthesize a series of novel indazole-7-carboxamide derivatives based on the structure of RBN-2397. Among these derivatives, (S)-XY-05 was identified as the most promising PARP7 inhibitor (IC 50 : 4.5 nM). Additionally, (S)-XY-05 showed enhanced selectivity toward PARP7 and improved pharmacokinetic properties (oral bioavailability: 94.60%) compared with RBN-2397 (oral bioavailability: 25.67%). In the CT26 syngeneic mouse model, monotherapy with (S)-XY-05 displayed a strong antitumor effect (TGI: 83%) by activating T-cell-mediated immunity within the tumor microenvironment. Collectively, we confirmed that (S)-XY-05 has profound effects on tumor immunity, which paves the way for future studies of PARP7 inhibitors that could be utilized in cancer immunotherapy.

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