Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives.

The TGFβ type II receptor (TβRII) is a central player in TGFβ signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFβ strategy. Especially its targeted degradation presents an excellent goal for effective TGFβ pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TβRII degrader chemotype was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping.

Rapid tissue prototyping with micro-organospheres.

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.

Development of Glucose Transporter (GLUT) Inhibitors.

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.

Small-Molecule Inhibition of Glucose Transporters GLUT-1-4.

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.

Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3.

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.

Inhibition of Glucose Transporters and Glutaminase Synergistically Impairs Tumor Cell Growth.

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.

Toward Second-Generation Cardiomyogenic and Anti-cardiofibrotic 1,4-Dihydropyridine-Class TGFβ Inhibitors.

Innovative therapeutic modalities for pharmacological intervention of transforming growth factor β (TGFβ)-dependent diseases are of great value. b-Annelated 1,4-dihydropyridines (DHPs) might be such a class, as they induce TGFβ receptor type II degradation. However, intrinsic drawbacks are associated with this compound class and were systematically addressed in the presented study.

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 identification and engagement are developed, but none of them is generic. Here we describe one of these techniques-the cellular thermal shift assay (CETSA).

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 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.