Structure-based design and discovery of potent and selective KDM5 inhibitors

Nie, Zhe; Shi, Lihong; Lai, Chon; O’Connell, Shawn M.; Xu, Jiangchun; Stansfield, Ryan; Hosfield, David J.; Veal, James M.; Stafford, Jeffrey A.

doi:10.1016/j.bmcl.2018.03.083

Cited by 35 publications

(15 citation statements)

References 17 publications

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“…Lysine-specific demethylase 5 (KDM5), also known as JARID1, consists of four family members, KDM5A, KDM5B, KDM5C, and KDM5D [ 13 ]. The KDM5 family contains five conserved domains: the catalytic JmjC domain, N-terminal JmjN domain, ARID domain, PHD finger domain, and the C5CH2 domain [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of Lysine-Specific Demethylase 5B (KDM5B) Promotes Tumor Cell Growth in Hep3B Cells and is an Independent Prognostic Factor in Patients with Hepatocellular Carcinoma

Gong

Yan

et al. 2018

Med Sci Monit

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BackgroundLysine-specific demethylase 5B (KDM5B) is overexpressed in several types of cancer. However, the clinical significance of KDM5B expression in hepatocellular carcinoma (HCC) remains unclear. The aims of the present study were to examine the functional effects of KDM5B in the Hep3B cell line, the expression levels of KDM5B in human HCC tissues, and the association between KDM5B expression and clinical outcome in patients with HCC.Material/MethodsImmunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression levels of KDM5B in HCC tissues and adjacent normal liver tissues. In the HCC cell line, Hep3B, the effects of KDM5B on cell proliferation and migration, and KDM5B small interfering RNA (siRNA) were used to study KDM5B knockdown. Univariate and multivariate analysis assessed the prognostic role of KDM5B in HCC patients. Kaplan-Meier analysis and the log-rank test evaluated clinical outcomes.ResultsIn the HCC cell line, Hep3B, KDM5B expression promoted promote tumor cell proliferation and colony formation. Increased expression of KDM5B in HCC tissues, compared with adjacent normal liver tissues, and was associated with larger tumor size, advanced TNM stage, and reduced overall survival in patients with HCC. Multivariate analysis identified KDM5B expression as an independent prognostic factor.ConclusionsIncreased expression of KDM5B was significantly correlated with poorer prognosis in patients with patients with HCC, indicating the possible potential of KDM5B as a novel clinical biomarker and therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Increased Expression of Lysine-Specific Demethylase 5B (KDM5B) Promotes Tumor Cell Growth in Hep3B Cells and is an Independent Prognostic Factor in Patients with Hepatocellular Carcinoma

Gong

Yan

et al. 2018

Med Sci Monit

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“…Ultimately the identification of such key alterations may help in clinical decision-making by identifying predictive biomarkers or new therapeutic targets. Indeed, several molecular inhibitors of the KDM5 family are currently under development, particularly in the setting of combination therapy and therapy resistance (Horton et al, 2016a,b;Vazquez-Rodriguez et al, 2018;Nie et al, 2018;Vinogradova et al, 2016;Johansson et al, 2016;Tumber et al, 2017;Bayo et al, 2018). Chemical inhibition of KDM5B as an anti-metastatic modality has not yet been tested.…”

Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes

Zoeller

Pedro

Konen

et al. 2019

Journal of Cell Science

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Collective invasion, the coordinated movement of cohesive packs of cells, has become recognized as a major mode of metastasis for solid tumors. These packs are phenotypically heterogeneous and include specialized cells that lead the invasive pack and others that follow behind. To better understand how these unique cell types cooperate to facilitate collective invasion, we analyzed transcriptomic sequence variation between leader and follower populations isolated from the H1299 non-small cell lung cancer cell line using an image-guided selection technique. We now identify 14 expressed mutations that are selectively enriched in leader or follower cells, suggesting a novel link between genomic and phenotypic heterogeneity within a collectively invading tumor cell population. Functional characterization of two phenotype-specific candidate mutations showed that ARP3 enhances collective invasion by promoting the leader cell phenotype and that wild-type KDM5B suppresses chain-like cooperative behavior. These results demonstrate an important role for distinct genetic variants in establishing leader and follower phenotypes and highlight the necessity of maintaining a capacity for phenotypic plasticity during collective cancer invasion.

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“…Previous studies have suggested KDM5A and KDM5B as oncogenic regulators [60]. The catalytic domain of KDM5 proteins has an unusual inclusion of an ARID and PHD1 domain that divides the catalytic domain into two subdomains-namely, JmjN and JmjC.…”

Section: New Synthesized Moleculesmentioning

confidence: 99%

Integration of Molecular Docking and In Vitro Studies: A Powerful Approach for Drug Discovery in Breast Cancer

Cava

Castiglioni

2020

Applied Sciences

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Molecular docking in the pharmaceutical industry is a powerful in silico approach for discovering novel therapies for unmet medical needs predicting drug–target interactions. It not only provides binding affinity between drugs and targets at the atomic level, but also elucidates the fundamental pharmacological properties of specific drugs. The purpose of this review was to illustrate newer and emergent uses of docking when combined with in vitro techniques for drug discovery in metastatic breast cancer. We grouped the selected articles into five main categories; namely, systematic repositioning of drugs, natural drugs, new synthesized molecules, combinations of drugs, and drug latentiation. We focused on new promising drugs that have a good affinity with their targets, thus inducing a favorable biological response. This review suggests that the integration of molecular docking and in vitro studies can accelerate cancer drug discovery showing a good consistency of the results between the two approaches.

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Structure-based design and discovery of potent and selective KDM5 inhibitors

Cited by 35 publications

References 17 publications

Increased Expression of Lysine-Specific Demethylase 5B (KDM5B) Promotes Tumor Cell Growth in Hep3B Cells and is an Independent Prognostic Factor in Patients with Hepatocellular Carcinoma

Increased Expression of Lysine-Specific Demethylase 5B (KDM5B) Promotes Tumor Cell Growth in Hep3B Cells and is an Independent Prognostic Factor in Patients with Hepatocellular Carcinoma

Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes

Integration of Molecular Docking and In Vitro Studies: A Powerful Approach for Drug Discovery in Breast Cancer

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