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Article
Open AccessOrpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP
Metabolic alterations in cancer precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product-inspired small molecules can provide a resource of invaluable ch...
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Article
Open AccessA divergent intermediate strategy yields biologically diverse pseudo-natural products
The efficient exploration of biologically relevant chemical space is essential for the discovery of bioactive compounds. A molecular design principle that possesses both biological relevance and structural div...
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Article
Open AccessDiscovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype
Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of protein function. In an attempt to explore protein degradation by means of ...
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Article
Open AccessProgramming inactive RNA-binding small molecules into bioactive degraders
Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules....
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Article
Open AccessNatural product fragment combination to performance-diverse pseudo-natural products
Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be...
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Article
Open AccessA protein tertiary structure mimetic modulator of the Hippo signalling pathway
Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical ...
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Article
Principle and design of pseudo-natural products
Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding s...
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Article
The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis
Autophagy mediates the degradation of damaged proteins, organelles and pathogens, and plays a key role in health and disease. Thus, the identification of new mechanisms involved in the regulation of autophagy ...
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Protocol
Target Engagement of Small Molecules: Thermal Profiling Approaches on Different Levels
The identification of protein targets and the elucidation of the molecular mechanism of action (MMoA) of bioactive small molecules are central goals of chemical biology. Many different techniques for target ident...
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Article
Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3
The principles guiding the design and synthesis of bioactive compounds based on natural product (NP) structure, such as biology-oriented synthesis (BIOS), are limited by their partial coverage of the NP-like c...
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Article
Open AccessNa+ entry through heteromeric TRPC4/C1 channels mediates (−)Englerin A-induced cytotoxicity in synovial sarcoma cells
The sesquiterpene (−)Englerin A (EA) is an organic compound from the plant Phyllanthus engleri which acts via heteromeric TRPC4/C1 channels to cause cytotoxicity in some types of cancer cell but not normal cells....
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Article
Small-molecule phenotypic screening with stem cells
To fully leverage the potential of human-induced pluripotent stem cells (hiPSCs), improved and standardized reprogramming methods and large-scale collections of hiPSC lines are needed, and the stem cell commun...
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Article
Open AccessA ligand-directed divergent catalytic approach to establish structural and functional scaffold diversity
The selective transformation of different starting materials by different metal catalysts under individually optimized reaction conditions to structurally different intermediates and products is a powerful app...
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Article
Open AccessIdentification of pyrazolopyridazinones as PDEδ inhibitors
The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and ...
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Article
Open AccessOrthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides
Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures ...
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Protocol
Identification of the Targets of Biologically Active Small Molecules Using Quantitative Proteomics
Currently, cell-based screenings yield a multitude of small molecule modulators of diverse biological processes. The most demanding step in the course of elucidation of the mode of action of biologically activ...
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Article
Small-molecule modulation of Ras signaling
There has been a strong effort to devise strategies to interfere with oncogenic Ras for cancer treatment. A review of recent advances in the development of small-molecule inhibitors that impair either Ras loca...
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Article
Fluorogenic probes for live-cell imaging of the cytoskeleton
Far-red fluorogenic probes for live-cell imaging of either actin or tubulin are described and used for super-resolution microscopy of various structures in a variety of cell types.
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Article
Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
KRAS is one of the most frequently mutated oncogenes and a major target in anticancer drug discovery, but small molecule modulators that work in the clinic have been elusive; here a new approach to target KRAS is...
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Chapter and Conference Paper
Hunting the Targets of Natural Product-Inspired Compounds
In evolution, nature has created a variety of secondary metabolites with high chemical and structural diversity. These natural products (NPs) were evolved by nature to exert particular biological functions and...
