Novel PARP7 Inhibitors for Treating Cancer

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

InfoMetricsFiguresRef. ACS Medicinal Chemistry LettersASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation referencesMore citation options ShareShare onFacebookXWeChatLinkedInRedditEmailBlueskyJump toExpandCollapse Patent HighlightMarch 20, 2025Novel PARP7 Inhibitors for Treating CancerClick copy article linkArticle link copied!Ram 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/0000-0001-7289-0581Open PDFACS LettersCite this: Med. Chem. Lett. 2025, XXXX, XXX, XXX-XXXClick citationCitation copied!https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00127https://doi.org/10.1021/acsmedchemlett.5c00127Published March 2025 Publication History Received 8 2025Published online 20 2025editorialPublished American Chemical Society. available under these Terms of Use. Request reuse permissionsAbstractClick section linkSection copied!High Resolution ImageDownload MS PowerPoint SlideProvided herein are novel inhibitors, pharmaceutical compositions, use such compounds in treating cancer processes preparing compounds.This licensed personal The PublicationsPublished SocietySubjectswhat subjects Article automatically applied from the Subject Taxonomy describe scientific concepts themes article. Alkyls Cancer Peptides proteins Pharmaceuticals Important Compound Classes TitlePARP7 NumberWO 2025/024663 A1 URLhttps://patents.google.com/patent/WO2025024663A1/en DateJanuary 30, Priority ApplicationUS 63/515,755 DateJuly 26, 2023 InventorsChang, J. J.; Chandrasekhar, Currie, K. S.; Holmbo, S. D.; Jacobsen, M.; Kukla, D. L.; Lee, H.; Moazami, Y.; Patel, L. B.; Paul, T. Perreault, Salvo, P. Treiberg, A.; Weaver, H. A. Assignee CompanyGilead Sciences Inc., USA Disease AreaCancer Biological TargetPARP7 SummaryThe poly(adenosine diphosphate-ribose) polymerase (PARP) family comprises 17 known enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, multiple stress responses, replication, recombination, chromatin remodeling, DNA damage repair. PARP1 PARP2 most extensively studied PARPs their role Inhibition PARP has been exploited as a strategy selectively kill cells inactivating complementary repair pathways.PARP7 acts negative regulator certain aryl hydrocarbon receptor (AHR) transcriptional targets. inhibitors have shown restore type I interferon (IFN) signaling responses nucleic acids causes tumor regression CT26 tumor-bearing, immunocompetent BALB/c mouse model.The present application describes series treatment cancer. Further, discloses compounds, preparation, use, composition, treatment. DefinitionsJ = ;X1 N, CR4 or CR4R4; X2 CR5; X3 X4 N X5 X6 CR5;Z 5–12 membered heteroaryl optionally substituted with one more R7, 6–10 C3–12 cycloalkyl 4–12 heterocyclyl R7;A O NH;R1 H, C1–6 alkyl, cycloalkyl;R2 halo, OH, -O(C1–6 alkyl), cyclopropyl; andR3a R3b alkyl). Key Structures AssayThe phospho-STAT1 (Tyr701) LANCE Ultra TR-FRET detection assay was performed. described were tested ability inhibit PARP7. EC50 (nM) following Table. DataThe Table below shows representative inhibition. biological data obtained testing examples listed ClaimsTotal claims: 39Compound 37Pharmaceutical composition 1Method 1 Recent Review ArticlesSee refs (1−6).Author InformationClick copied!Corresponding AuthorRam Sabnis, Smith, States, https://orcid.org/0000-0001-7289-0581, Email: protected]NotesThe author declares no competing financial interest.ReferencesClick copied! references 6 other publications. 1Wang, Zhang, Wu, X.; Huang, Xiao, W.; Guo, C. potential antitumor drugs perspective molecular design. 68, 18– 48, DOI: 10.1021/acs.jmedchem.4c02642 Google ScholarThere corresponding record reference.2Wang, Zeng, T.; Chen, Xu, B. Parps immune response: Potential targets immunotherapy. Biochem. Pharmacol. 234, 116803, 10.1016/j.bcp.2025.116803 reference.3Duan, Gao, Li, Ren, Liao, Y. Targeting selective drug discovery development. Res. 2024, 33, 1734– 1756, 10.1007/s00044-024-03282-4 reference.4Liang, Peng, X. Overview epigenetic/cytotoxic dual-target therapy. Eur. 285, 117235, 10.1016/j.ejmech.2024.117235 reference.5Sabnis, R. Novel 2023, 14, 1615– 1616, 10.1021/acsmedchemlett.3c00458 reference.6Liu, Pillai, Leung, ADP-ribosylation-mediated biomolecular condensates: determinants, dynamics, disease implications. Trends Sci. 50, 224– 241, 10.1016/j.tibs.2024.12.013 reference.Cited By Click copied!This not yet cited publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS copied!https://doi.org/10.1021/acsmedchemlett.5c00127Published permissionsArticle Views-Altmetric-Citations-Learn about metrics closeArticle Views COUNTER-compliant sum full text downloads since November 2008 (both PDF HTML) across all institutions individuals. These regularly updated reflect usage leading up last few days.Citations number articles citing article, calculated Crossref daily. Find information counts.The Altmetric Attention Score quantitative measure attention research received online. Clicking on donut icon will load page at altmetric.com additional details score social media presence given how calculated.Recommended Articles FiguresReferencesAbstractHigh SlideReferences There reference.

Язык: Английский

Discovery and Optimization of Potent and Highly Selective PARP14 Inhibitors for the Treatment of Atopic Dermatitis

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

Atopic dermatitis (AD) is a chronic, recurrent, and inflammatory skin condition that remains challenging to treat effectively safely with current therapies. Recent studies by multiple independent research groups have demonstrated poly(ADP-ribose) polymerase 14 (PARP14) has been implicated in the progression of diseases through its regulation Th2 Th17 signaling pathways, leading identification PARP14 as promising therapeutic target. Herein, we report discovery novel inhibitor Q22 exceptional inhibitory activity against (IC50 = 5.52 nM), high selectivity toward PARP14, favorable pharmacokinetic properties, robust vivo safety profile. Notably, compared positive control RBN-3143, showed significant efficacy dinitrochlorobenzene (DNCB)-induced AD mouse model markedly reducing expression key AD-associated cytokines, including IL-4, IL-13, IL-17A. These findings suggest holds considerable promise for treatment.

Язык: Английский