Inhibitors and PROTACs of CDK2: challenges and opportunities

Expert Opinion on Drug Discovery, Год журнала: 2024, Номер 19(9), С. 1125 - 1148

Опубликована: Июль 12, 2024

Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation cancer cells. Thus, CDK2 has become a promising therapeutic target for treatment. In recent years, insights into structures catalytic site and allosteric pockets have provided notable opportunities developing more effective clinical candidates inhibitors.

Язык: Английский

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Effects of Garlic on Breast Tumor Cells with a Triple Negative Phenotype: Peculiar Subtype-Dependent Down-Modulation of Akt Signaling

Cells, Год журнала: 2024, Номер 13(10), С. 822 - 822

Опубликована: Май 11, 2024

Breast cancer includes tumor subgroups with morphological, molecular, and clinical differences. Intrinsic heterogeneity especially characterizes breast tumors a triple negative phenotype, often leading to the failure of even most advanced therapeutic strategies. To improve treatment, use natural agents integrate conventional therapies is subject ever-increasing attention. In this context, garlic (Allium sativum) shows anti-cancerous potential, interfering proliferation, motility, malignant progression both non-invasive invasive cells. As could be at basis variable effects, main objective our study was evaluate anti-tumoral activity extract in cells phenotype. Established (TNBC) cell lines from patient-derived xenografts (PDXs) were used, revealing subtype-dependent effects on morphology, cycle, correlated peculiar down-modulation Akt signaling, crucial regulator solid tumors. Our results first demonstrate that TNBC are not unique suggest only more precise knowledge mechanisms activated by compound each will allow for inclusion personalized approaches cancer.

Язык: Английский

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Structure activity relationship for anticancer activities of spirooxindole derivatives: A comprehensive review

Bioorganic Chemistry, Год журнала: 2024, Номер 154, С. 107975 - 107975

Опубликована: Ноя. 19, 2024

Язык: Английский

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Toward Precision Oncology: The Role of TPD in Targeting CDK2 and Beyond

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(7), С. 1004 - 1006

Опубликована: Июнь 24, 2024

Advancements in targeted protein degradation (TPD) technologies are spearheading a new era precision oncology, offering unprecedented avenues for tackling key oncogenic drivers such as Cyclin-dependent kinase 2 (CDK2). As pivotal regulator of the cell cycle, CDK2's aberrant activity is closely linked with cancer progression, making it prime target therapeutic intervention. This Patent Highlight delves into innovative TPD strategies aimed at CDK2 degradation, illustrating their potential to disrupt proliferation and reshape landscape significantly. By extending focus other critical proteins within biology, discussion emphasizes technologies' versatility transformative delivering targeted, efficacious therapies.

Язык: Английский

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Identification of the potential Pan-CDK antagonists: tracing the path of virtual screening and inhibitory activity on lung cancer cells

Molecular Diversity, Год журнала: 2024, Номер unknown

Опубликована: Июль 29, 2024

Язык: Английский

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HDAC inhibitors modulate Hippo pathway signaling in hormone positive breast cancer

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Окт. 15, 2024

Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is majority subtype. Histone deacetylase (HDAC) inhibitors have shown clinical benefit HR (+) breast patients. The hippo pathway proteins YAP/TAZ are often viewed as pro-tumorigenic, however, recent studies support a role YAP tumor suppressor downregulation estrogen (ER) expression. Few investigated link between HDACi Hippo pathway. In our study, we demonstrate that HDAC induce transcriptional down-regulation expression, while conversely activating TEAD mediated program with upregulation canonical genes. We further identified 4 genes (CCDC80, GADD45A, F3, TGFB2) were upregulated by associated significantly improved survival cohort. Patients high CCDC80 or GADD45A expression had better outcomes compared to patients low Our study provides novel mechanism action for inhibitors, providing experimental Hippo-TEAD activation cancer.

Язык: Английский

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Discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as anticancer agents: virtual screening and molecular dynamic studies

SAR and QSAR in environmental research, Год журнала: 2024, Номер unknown, С. 1 - 33

Опубликована: Ноя. 28, 2024

CDK/Cyclins are dysregulated in several human cancers. Recent studies showed inhibition of CDK4/6 was responsible for controlling cell cycle progression and cancer growth. In the present study, atom-based field-based 3D-QSAR, virtual screening, molecular docking dynamics were done development novel pyrrolo[2,3-d]pyrimidine (P2P) derivatives as anticancer agents. The developed models good

Язык: Английский

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Novel Compounds as CDK2 Inhibitors for Treating Cancer

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 16(1), С. 14 - 15

Опубликована: Дек. 10, 2024

InfoMetricsFiguresRef. ACS Medicinal Chemistry LettersASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse Patent HighlightDecember 10, 2024Novel Compounds as CDK2 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. 2024, XXXX, XXX, XXX-XXXClick citationCitation copied!https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00574https://doi.org/10.1021/acsmedchemlett.4c00574Published December 2024 Publication History Received 24 November 2024Published online 10 2024editorialPublished American Chemical Society. available under these Terms of Use. Request reuse permissionsAbstractClick section linkSection copied!High Resolution ImageDownload MS PowerPoint SlideProvided herein are novel compounds inhibitors, pharmaceutical compositions, use such in treating cancer, processes preparing compounds.This licensed personal The PublicationsPublished Society Important Compound Classes TitleCyclin-Dependent Kinase (CDK2) NumberWO 2024/171094 A1URL: https://patents.google.com/patent/WO2024171094A1/en DateAugust 22, Priority ApplicationsUS 63/485,709 US 63/580,277 DatesFebruary 17, 2023, September 1, 2023 InventorsBriner, K.; Chen, X.; Joseph, S.; Rauniyar, V.; Zecri, F. Assignee CompanyNovartis AG, Switzerland Disease AreaCancer Biological TargetCDK2 SummaryCyclic-dependent kinase 2 a serine/threonine that regulates the mammalian cell cycle. After binding cyclin-E1, cyclin-E2, cyclin-A1, or cyclin-A2, activated CDK2–cyclin complex phosphorylates variety cellular substrates. its activity often dysregulated human cancers. One dysregulation mechanism involves amplification overexpression which leads hyperactivation promotes proliferation. Cyclin-E1 also associated with poor prognosis across In many cancers, besides radiation chemotherapy, there no targeted therapy patients. Thus, development agent against would potentially benefit cancer patients.The present application describes series inhibitors treatment cancer. Further, discloses compounds, their preparation, use, composition, treatment. DefinitionsY1 = bond CH2;Y2 bond, O, NR5 CR6R7;R1 R2 H, halo, C1–C6alkyl C1–C6haloalkyl;R3 hydroxy, C1–C6haloalkyl;R4 C1–C6haloalkyl;ring A 5 membered heteroaryl comprising 1 3 heteroatoms selected from N, O S, said being substituted 0 substituents RA;m 5; n 3. Key Structures AssayThe biochemical assay was performed. described were tested ability inhibit CDK2. IC50 values (μM) shown following table. DataThe table below shows representative inhibition biological data obtained testing examples. ClaimsTotal claims: 49Compound 42Pharmaceutical composition 1Method 3Method modulation 1Use compound Recent Review ArticlesSee refs (1−5).Author InformationClick copied!Corresponding AuthorRam Sabnis, Smith, States, https://orcid.org/0000-0001-7289-0581, Email: protected]NotesThe author declares competing financial interest.ReferencesClick copied! references other publications. 1Patel, D. A.; Patel, S. H. Advances synthesis evaluation therapy. Bioorg. 143, 107045, DOI: 10.1016/j.bioorg.2023.107045 Google ScholarThere corresponding record reference.2Gerosa, R.; De Sanctis, Jacobs, F.; Benvenuti, C.; Gaudio, M.; Saltalamacchia, G.; Torrisi, Masci, Miggiano, Agustoni, Pedrazzoli, P.; Santoro, Zambelli, A. Cyclin-dependent others CDK (CDKi) breast cancer: clinical trials, current impact, future directions. Crit. Rev. Oncol. Hematol. 196, 104324, 10.1016/j.critrevonc.2024.104324 reference.3Morrison, L.; Loibl, Turner, N. C. CDK4/6 inhibitor revolution – game-changing era Nat. Clin. 21, 89– 105, 10.1038/s41571-023-00840-4 reference.4Areewong, Suppramote, O.; Prasopporn, Jirawatnotai, Exploiting acquired vulnerability develop treatments cholangiocarcinoma. Cancer Cell Int. 24, 362, 10.1186/s12935-024-03548-2 reference.5Sabnis, R. Sulfonylamide Cancer. 2021, 12, 1528– 1529, 10.1021/acsmedchemlett.1c00471 reference.Cited By Click copied!This has not yet been cited publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS copied!https://doi.org/10.1021/acsmedchemlett.4c00574Published permissionsArticle Views225Altmetric-Citations-Learn about metrics closeArticle Views COUNTER-compliant sum full text downloads since 2008 (both PDF HTML) all institutions individuals. These regularly updated reflect usage leading up last few days.Citations number articles citing article, calculated Crossref daily. Find more 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 article. how calculated.Recommended Articles FiguresReferencesAbstractHigh SlideReferences There reference.

Язык: Английский

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Targeting autophagy plus high-dose CDK4/6 inhibitors in advanced HR+HER2− breast cancer: A phase 1b/2 trial

Med, Год журнала: 2024, Номер unknown, С. 100559 - 100559

Опубликована: Дек. 1, 2024

Язык: Английский

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