Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles

Liu, Jie; Mallick, Shubhadip; Xie, Yusheng; Grassin, Corentin; Lucas, Belén; Schölermann, Beate; Pahl, Axel; Scheel, Rebecca; Strohmann, Carsten; Protzel, Christoph; Berg, Thorsten; Merten, Christian; Ziegler, Slava; Waldmann, Herbert

doi:10.1002/anie.202301955

Cited by 5 publications

(4 citation statements)

References 60 publications

(37 reference statements)

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“…The isatin-derived tosylhydrazone 2 and the diazo isatin 3 are prepared according to a known procedure starting from substituted isatins [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

“…The purity of biologically evaluated compounds was >95% as determined by HPLC analysis (Waters e2695, C18 column (50 × 2.00 mm), with CH 3 OH and H 2 O as the mobile phase, monitored by UV absorption at 231 nm). The isatin-derived tosylhydrazone 2 and the diazo isatin 3 are prepared according to a known procedure starting from substituted isatins [48].…”

Section: Experimental Section 41 General Methods and Materialsmentioning

confidence: 99%

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Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Zheng,

Yang,

et al. 2023

Molecules

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An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 μM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.

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“…The isatin-derived tosylhydrazone 2 and the diazo isatin 3 are prepared according to a known procedure starting from substituted isatins [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Experimental Section 41 General Methods and Materialsmentioning

confidence: 99%

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Zheng,

Yang,

et al. 2023

Molecules

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“…Recently in 2023, a study by Liu et al identified the mitotic kinesin, Eg5, as the molecular target for spirooxindoles-unique inhibitors of the kinesin Eg5 chemotype. 92 Overall, phenotypic profiling enables the bioactivity and MoA of diversity-oriented synthesized compounds to be predicted based on their similarities with reference compound activity profiles, which in many cases, can reveal new chemical scaffolds of interest.…”

Section: Phenotypic Profiling Of Structurally Diverse Compoundsmentioning

confidence: 99%

A Decade in a Systematic Review: The Evolution and Impact of Cell Painting

Seal,

Trapotsi,

Spjuth

et al. 2024

Preprint

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High-content image-based assays have fueled significant discoveries in the life sciences in the past decade (2013-2023), including novel insights into disease etiology, mechanism of action, new therapeutics, and toxicology predictions. Here, we systematically review the substantial methodological advancements and applications of Cell Painting. Advancements include improvements in the Cell Painting protocol, assay adaptations for different types of perturbations and applications, and improved methodologies for feature extraction, quality control, and batch effect correction. Moreover, machine learning methods recently surpassed classical approaches in their ability to extract biologically useful information from Cell Painting images. Cell Painting data have been used alone or in combination with other - omics data to decipher the mechanism of action of a compound, its toxicity profile, and many other biological effects. Overall, key methodological advances have expanded Cell Painting’s ability to capture cellular responses to various perturbations. Future advances will likely lie in advancing computational and experimental techniques, developing new publicly available datasets, and integrating them with other high-content data types.

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“…These profiles can be compared to the profiles of reference compounds with annotated biological activities to generate target or mode of action hypotheses. [33,34] Activity in the CPA can be expressed as an induction value, which is the percentage of significantly changed features in a profile relative to DMSO controls (see Supporting Information section 'Cell Painting Assay' for more details). [32] Profiles with � 5 % induction are considered to be CPA-active.…”

Section: Biological Evaluationmentioning

confidence: 99%

Collective Synthesis of Sarpagine and Macroline Alkaloid‐Inspired Compounds

Aoyama,

Davies,

Liu

et al. 2023

Chemistry A European J

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Design strategies that can access natural product‐like chemical space in an efficient manner may facilitate the discovery of biologically relevant compounds. We have employed a divergent intermediate strategy to construct an indole‐alkaloid inspired compound collection derived from two different molecular design principles, i.e. biology‐oriented synthesis and pseudo‐natural products. The divergent intermediate was subjected to acid‐catalyzed or newly discovered Sn‐mediated conditions to selectively promote intramolecular C‐ or N‐acylation, respectively. After further derivatization, a collection totalling 84 compounds representing four classes was obtained. Morphological profiling via the cell painting assay coupled with a subprofile analysis showed that compounds derived from different design principles have different bioactivity profiles. The subprofile analysis suggested that a pseudo‐natural product class is enriched in modulators of tubulin, and subsequent assays led to the identification of compounds that supress in vitro tubulin polymerization and mitotic progression.

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Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles

Cited by 5 publications

References 60 publications

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

A Decade in a Systematic Review: The Evolution and Impact of Cell Painting

Collective Synthesis of Sarpagine and Macroline Alkaloid‐Inspired Compounds

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