Design, Synthesis, and Biological Evaluation of a Series of Benzofuran [3,2-D]Pyrimidine-4(1h)-Ketone Derivatives Containing Thiosemicarbazone Analogs as Novel Parp-1 Inhibitors DOI
Yuanjiang Wang, Kun Li, Wenqing Xu

et al.

Published: Jan. 1, 2023

Poly ADP ribose polymerase-1 (PARP-1) plays a crucial role in processes such as DNA damage repair, gene transcription, and cell apoptosis cancer cells. Therefore, PARP-1 represents promising target to develop anticancer drugs. By summarizing the structure-activity relationship of inhibitors, series benzofuran [3,2-D]pyrimidine-4(1H)-ketone derivatives containing thiosemicarbazide or its analogs were designed, synthesized biologically evaluated on their inhibition PARP enzyme activity. Among all compounds, 19c exhibited superior biological activity with IC50 values 22 nM 4.98 μM for exogenous SK-OV-3 cells, respectively, better than Olaparib. In addition, showed low toxicity normal liver Anti-cancer mechanism studies revealed that could inhibit repair single-strand breakage aggravate double-strand by inhibiting activity, promote cells through mitochondrial pathway. all, these complexes may have potential novel inhibitors.

Language: Английский

Hematological Toxicities with PARP Inhibitors in Prostate Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials DOI Open Access
Gartrell C. Bowling,

Piragash Swargaloganathan,

C. Heintz

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(19), P. 4904 - 4904

Published: Oct. 9, 2023

Background: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments mCRPC, PARPis not without drug-related hematological adverse events. Objective: To review the evidence on toxicities, including anemia, thrombocytopenia, and neutropenia from in cancer. Study Methodology: A systematic meta-analysis using PRISMA guidelines was performed phase II III randomized controlled trials (RCTs) PubMed, Embase, Ovid All EBM reviews—Cochrane were queried inception to 9 June 2023. The Mantel–Haenszel method used report risk ratios (RR) 95% confidence intervals (CI) all-grade high-grade toxicities. Results: retrieved eight RCTs; specifically, included five thrombocytopenia neutropenia, four outcomes. Compared a placebo and/or other non-PARPi treatments, PARPi use associated with increased anemia (RR, 3.37; CI, 2.37–4.79; p < 0.00001), 4.54; 1.97–10.44; = 0.0004), 3.11; 1.60–6.03; 0.0008). High-grade 6.94; 4.06–11.86; 0.00001) 5.52; 2.80–10.88; also risk, while 3.63; 0.77–17.23; 0.10) showed no significant association. Subgroup stratification analyses differences various Conclusion: AEs. Future studies more pooled RCTs will enhance this understanding continue inform patient–physician shared decision-making. may have role improving current management strategies these

Language: Английский

Citations

3
Novel PARP7 Inhibitors for Treating Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(12), P. 1615 - 1616

Published: Nov. 4, 2023

ADVERTISEMENT RETURN TO ISSUEPREVPatent HighlightNEXTNovel PARP7 Inhibitors for Treating CancerRam W. Sabnis*Ram SabnisSmith, Gambrell & Russell LLP, 1105 Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States*E-mail: [email protected]More by Ram Sabnishttps://orcid.org/0000-0001-7289-0581Cite this: ACS Med. Chem. Lett. 2023, 14, 12, 1615–1616Publication Date (Web):November 4, 2023Publication History Received14 October 2023Published online4 November inissue 14 December 2023https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00458https://doi.org/10.1021/acsmedchemlett.3c00458editorialACS PublicationsCopyright © Published 2023 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions free to access through this site. Learn MoreArticle Views1205Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum full text article downloads since 2008 (both PDF and HTML) across all institutions individuals. These metrics regularly updated reflect usage leading up last few days.Citations number other articles citing article, calculated Crossref daily. Find more information about citation counts.The Altmetric Attention Score a quantitative measure attention that research has received online. Clicking on donut icon will load page at altmetric.com with additional details score social media presence given article. how calculated. Share Add toView InAdd Full Text ReferenceAdd Description ExportRISCitationCitation abstractCitation referencesMore Options onFacebookTwitterWechatLinked InRedditEmail (987 KB) Get e-AlertscloseSUBJECTS:Cancer,Hydrocarbons,Inhibitors,Peptides proteins,Pharmaceuticals e-Alerts

Language: Английский

Citations

3
Prostatic adenocarcinoma: molecular underpinnings and treatment-related options DOI

Divyangi Paralkar,

Amir Akbari,

Manju Aron

et al.

Urologic Oncology Seminars and Original Investigations, Journal Year: 2024, Volume and Issue: 42(7), P. 203 - 210

Published: March 19, 2024

Language: Английский

Citations

0
Treatment of Castration-Resistant Prostate Cancer DOI Creative Commons
Zoran Todorović

Prostate Cancer, Journal Year: 2024, Volume and Issue: unknown, P. 389 - 397

Published: Jan. 1, 2024

Castration-resistant prostate cancer (CRPC) is a major therapeutic problem. Resistance to androgen deprivation therapy occurs in many patients after initial success. The tumor develops genetic and epigenetic mechanisms by which it successfully bypasses the effects of applied (mutation gene for receptor enzymes synthesis, splice forms receptor, loss production antitumor proteins, and/or increased creation proteins that stimulate formation tumors, etc.). As drugs, CRPC, we have second-generation antagonists such as darolutamide, followed abiraterone, newer options like pembrolizumab olaparib.

Language: Английский

Citations

0
PACT is requisite for prostate cancer cell proliferation DOI Creative Commons
Peter J. Leedman, Dianne J. Beveridge, Andrew J. Woo

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: April 25, 2024

Abstract PACT (encoded by the PRKRA gene) is a double-stranded RNA binding protein that has two main functions in mammals: facilitation of antiviral defense mechanisms via activation kinase (PKR) and retinoic acid-inducible gene 1 (RIG-1), also member cytoplasmic RNA-induced silencing complex. We previously described an alternate role for as modulator nuclear receptor (NR)-regulated expression. Here, we investigated prostate cancer (PCa) using loss-of-function approach. Depletion PCa cell lines resulted reduction proliferation; however, they were viable. RNA-sequencing analysis LNCaP cells ± revealed depletion biological processes involved cycle, mitochondrial function, NR-response pathways knockout (KO) cells. In KO cells, downregulated genes included H2AFJ, PSMD5, AQP3, TMEM45B, SLC22A3, and KLK3 (prostate specific antigen, PSA), siRNA mediated knockdown these reduced growth proliferation Taken together, data provide support proproliferative targeting PRKRA, or are therapies, could benefit patient survival.

Language: Английский

Citations

0
Future Landscape in High-risk Prostate Cancer and Metastatic Prostate Cancer DOI Creative Commons
Harshit Garg, Dharam Kaushik, Michael A. Liss

et al.

UroCancer Clinics of India ., Journal Year: 2024, Volume and Issue: 2(1), P. 37 - 44

Published: Jan. 1, 2024

Summary The management of high-risk and advanced prostate cancer had a major paradigm shift over the past decade. From Huggins’ era sole androgen deprivation therapy (ADT), has evolved to novel receptor signaling inhibitors (ARSI), chemotherapy, targeted molecular, immunotherapy, radiotheranostics. is broadly studied under metastatic hormone or castration-sensitive (mCSPC) castration-resistant (mCRPC). mCSPC from mere ADT use abiraterone, enzalutamide, docetaxel-based chemotherapy burning conflict treatment intensification with triplet therapy. Various agents, such as poly (ADP-ribose) polymerase (PARPIs) radiotheranostics, are being explored in mCSPC. mCRPC mitoxantrone therapy, ARSI PARPI, 177 lutetium-prostate-specific membrane antigen-617, novel-targeted

Language: Английский

Citations

0
Inhibitory function of CDK12i combined with WEE1i on castration-resistant prostate cancer cells in vitro and in vivo DOI Creative Commons
Qin Zheng, Dongze Liu,

Yueyao Zhang

et al.

ONCOLOGIE, Journal Year: 2023, Volume and Issue: 25(6), P. 717 - 728

Published: Aug. 7, 2023

Abstract Objective The inhibitors of CDK12 and WEE1 (SR-4835 AZD-1775) have rarely been evaluated in studies on castration-resistant prostate cancer (CRPC) treatment. research objective this article is to study the inhibitory effect SR-4835 AZD-1775 CRPC cells explore therapeutic combining two drugs treatment vitro vivo . Methods We performed Western blot, quantitative real-time PCR, Cell Counting Kit-8, colony formation, EdU, immunofluorescence assays; cell cycle analysis, wound scratch Transwell assays nude mice xenograft tumor analysis identify mechanism measure SR-4835, combination cells. Results Compared with normal cells, expressions especially were significantly increased at protein mRNA levels. can cause DNA damage by inhibiting expression repair genes. inhibits G2/M phase checkpoint function. Performing experiments, we found that combined enhanced a greater degree than monotherapy. Conclusions In summary, eliminate inducing machinery. Therefore, consider therapy be promising strategy for patients.

Language: Английский

Citations

1
Design, Synthesis, and Biological Evaluation of a Series of Benzofuran [3,2-D]Pyrimidine-4(1h)-Ketone Derivatives Containing Thiosemicarbazone Analogs as Novel Parp-1 Inhibitors DOI
Yuanjiang Wang, Kun Li, Wenqing Xu

et al.

Published: Jan. 1, 2023

Poly ADP ribose polymerase-1 (PARP-1) plays a crucial role in processes such as DNA damage repair, gene transcription, and cell apoptosis cancer cells. Therefore, PARP-1 represents promising target to develop anticancer drugs. By summarizing the structure-activity relationship of inhibitors, series benzofuran [3,2-D]pyrimidine-4(1H)-ketone derivatives containing thiosemicarbazide or its analogs were designed, synthesized biologically evaluated on their inhibition PARP enzyme activity. Among all compounds, 19c exhibited superior biological activity with IC50 values 22 nM 4.98 μM for exogenous SK-OV-3 cells, respectively, better than Olaparib. In addition, showed low toxicity normal liver Anti-cancer mechanism studies revealed that could inhibit repair single-strand breakage aggravate double-strand by inhibiting activity, promote cells through mitochondrial pathway. all, these complexes may have potential novel inhibitors.

Language: Английский

Citations

0