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The TGFß type II receptor (TßRII) is a central player in all TGFß signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFß strategy. Especially its targeted degradation presents an excellent goal for effective TGFß pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TßRII degrader chemotype 1 was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping. Two distinct 3,4-disubstituted indoles were identified from virtual screening: tetrahydro-4-oxo-indole 2 and indole-3-acetate 3. Design, synthesis, and screening of focused amide libraries confirmed 2r and 3n as potent TGFß inhibitors. They were validated to fully recapitulate the ability of 1 to selectively degrade TßRII, without affecting TßRI. Consequently, 2r and 3n efficiently blocked endothelial-to-mesenchymal transition and cell migration in different cancer cell lines while not perturbing the microtubule network. Hence, 2 and 3 present novel TßRII degrader chemotypes that will (1) aid target deconvolution efforts and (2) accelerate proof-of-concept studies for small-molecule-driven TßRII degradation in vivo.

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In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applications including quantitative assessment of nutrient dependence, pathogen-host interaction for anti-viral drug screening, and a rapid potency assay for chimeric antigen receptor (CAR)-T therapy. An automated MOS imaging pipeline combined with machine learning overcomes plating variation, distinguishes tumorspheres from stroma, differentiates cytostatic versus cytotoxic drug effects, and captures resistant clones and heterogeneity in drug response. This pipeline is capable of robust assessments of drug response at individual-tumorsphere resolution and provides a rapid and high-throughput therapeutic profiling platform for precision medicine.

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The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells. This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction.

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Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose-dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform-selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.

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Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage of NP-like chemical space and biological target space. These limitations can be overcome by combining NP-centered strategies with fragment-based compound design through combination of NP-derived fragments to afford structurally unprecedented "pseudo-natural products" (pseudo-NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo-NPs that combine biosynthetically unrelated indole- and morphan-alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT-1 and GLUT-3. Glupin suppresses glycolysis, reduces the levels of glucose-derived metabolites, and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT-1 and GLUT-3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.

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Cancer cells sustain growth by altering their metabolism to accelerated aerobic glycolysis accompanied by increased glucose demand and employ glutamine as additional nutrient source. This metabolic adaptation induces upregulation of glucose transporters GLUT-1 and -3, and simultaneous targeting of both transporters and of glutamine metabolism may offer a promising approach to inhibit cancer cell growth. We describe the discovery of the very potent glucose uptake inhibitor Glutor, which targets glucose transporters GLUT-1, -2, and -3, attenuates glycolytic flux and potently and selectively suppresses growth of a variety of cancer cell lines. Co-treatment of colon cancer cells with Glutor and glutaminase inhibitor CB-839 very potently and synergistically inhibits cancer cell growth. Such a dual inhibition promises to be particularly effective because it targets the metabolic plasticity as well as metabolic rescue mechanisms in cancer cells.

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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 identification and engagement are developed, but none of them is generic. Here we describe one of these techniques-the cellular thermal shift assay (CETSA). The assay works without any labeling of proteins or small molecules, which allows the investigation of the unaltered interaction between the interaction partners. Briefly, the influence of small molecules on the thermal stability of proteins within whole cell lysates is investigated. We describe this approach in two variants: the conventional immunoblot-based approach (CETSA), as well as an unbiased approach based on a proteome-wide mass spectrometric analysis (thermal proteome profiling, TPP). The CETSA approach requires preknowledge about possible target proteins and can only detect a few proteins at once. Although TPP is technically more demanding, it allows for the identification of multiple (off)targets without any preknowledge.

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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 chemical space of existing NPs and retainment of bioactivity in the corresponding compound collections. Here we propose and validate a concept to overcome these limitations by de novo combination of NP-derived fragments to structurally unprecedented 'pseudo natural products'. Pseudo NPs inherit characteristic elements of NP structure yet enable the efficient exploration of areas of chemical space not covered by NP-derived chemotypes, and may possess novel bioactivities. We provide a proof of principle by designing, synthesizing and investigating the biological properties of chromopynone pseudo NPs that combine biosynthetically unrelated chromane- and tetrahydropyrimidinone NP fragments. We show that chromopynones define a glucose uptake inhibitor chemotype that selectively targets glucose transporters GLUT-1 and -3, inhibits cancer cell growth and promises to inspire new drug discovery programmes aimed at tumour metabolism.

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