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Natural product–inspired compounds are primed to interact with and manipulate biological processes, but obtaining these complex molecules poses synthetic challenges. The development of a 12-step, 1-pot cascade reaction leads to the 'centrocountins', tetrahydroindoloquinolizines that modulate mitosis by targeting the centrosome-associated proteins nucleophosmin and Crm1.

Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

Natural products populate areas of chemical space not occupied by average synthetic molecules. Here, an analysis of more than 180,000 natural product structures results in a library of 2,000 natural-product-derived fragments, which resemble the properties of the natural products themselves and give access to novel inhibitor chemotypes.

New methods for targeted covalent protein modification at low reactivity aspartates and glutamates are of high interest. Here, the authors report a technique inspired by the HaloTag technology, which employs a covalent conjugation reaction between ligands with a reactive chloroalkane linker and a specific aspartic acid, and use it to covalently modify lipoprotein chaperone PDEδ at a binding site glutamic acid.

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

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 described, based on interfering with its binding to the prenyl-binding protein PDEδ.

As Nature Chemical Biology approaches its third decade we asked a collection of chemical biologists, “What do you think are the most exciting frontiers or the most needed developments in your main field of research?” — here is what they said.

Small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

Chemical, genetic and proteomic approaches were used to elucidate the mode of action of orpinolide, a withanolide-inspired OSBP inhibitor, revealing sterol transport as a druggable metabolic dependency in leukemia.

Design strategies that possess both biological relevance and structural diversity may lead to compound collections that are enriched in diverse bioactivities. Now a diverse pseudo-natural product design principle has been established to efficiently explore biologically relevant chemical space. Through dearomatization reactions, a compound collection enriched in both structural and biological diversity was rapidly generated.

Targeted protein degradation (TPD) has emerged as a new paradigm for modulating protein activity. Here, the authors develop bifunctional degraders combining a putative ligand of the autophagy-related LC3 protein with different protein targets, which direct proteins of interest to the proteasome by covalently targeting the DCAF11 E3 ligase substrate receptor.

A chemical genetics approach identifies the Raf-MEK-ERK signaling system downstream of PKC in formation of the antimicrobial cell structures called neutrophil extracellular traps.

Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.

PDEδ is a widely expressed factor that sustains the spatial organization and signalling of Ras family proteins. Here the authors describe the activity of Deltazinone 1, a new highly selective PDEδ inhibitor of KRAS-dependent cancer cell growth with low cytotoxic side effects.

Bicyclic peptides can inhibit biological targets hard to address with small molecules. Here, the authors combine two orthogonal ring-closing reactions to produce bicyclic peptides with improved bioactivity thereby providing a strategy that can greatly improve the structural diversity of such peptides.

Syntheses of natural product–like compound libraries with high scaffold diversity have proven hard to develop. A strategy employing metathesis cascades to 'zip up' a set of unsaturated building blocks differently connected by variable linkers demonstrates that over 80 distinct scaffold classes can be synthesized in one go.

New natural-product-inspired molecules are often limited by their only partial coverage of biologically relevant chemical space. Combining fragments of natural products has now been shown to yield pseudo natural products, which — while still being inspired by natural products — populate previously unexplored areas of chemical space and have novel biological activities.

The cholesterol-transfer protein GRAMD1A is identified as the target of the autophagy inhibitors autogramin-1 and autogramin-2. GRAMD1A is found to be required for autophagosome biogenesis.

Reversible palmitoylation controls the localization and signaling of Ras. Development of a potent and specific small molecule inhibitor of the thioesterase APT1 reveals that this enzyme depalmitoylates Ras in cells. Inhibition of APT1 led to redistribution and altered activity of HRas, NRas and an oncogenic mutant Ras.

Synthetic methods that efficiently construct structurally diverse molecular scaffolds are attractive routes to diversely bioactive molecules. Here the authors report a method whereby common starting materials are converted to structurally and functionally diverse products by changing the catalyst ligand.

A Lewis-acid-catalysed 1,3-dipolar cycloaddition provides rapid access to a variety of substituted spirooxindoles. Initial cellular evaluations supports the view that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry, and decorated with assorted substituents, will be a rich source of compounds with diverse bioactivity.

Searching chemical space for biologically active molecules requires facile access to new molecular architectures. Variations in reagent, catalyst and reaction order create a programmable one-pot method that yields single stereoisomers of complex cycloadducts, including either isomer of enantiomeric pairs.

Trafficking G proteins between membranes is essential for their signaling activity. Structural and biochemical studies on the farnesylated G protein Rheb and the guanine nucleotide–dissociation inhibitor (GDI)-like PDEδ suggest an allosteric mechanism for Rheb release and identify a bona fide GDI-displacement factor (GDF).

Semisynthetic versions of the small G protein Rab7 in the GDP-bound form have 1,000-fold higher affinity for regulators REP1 and RabGDI because of faster dissociation rates from Rab7-GTP, directly linking nucleotide exchange to Rab membrane targeting.

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 community must embrace chemical biology methodology for target identification and validation.

Mir-138, identified in a screen for microRNAs associated with synapses, regulates dendritic spine morphogenesis through APT-1, a depalmitoylation enzyme that modulates the membrane localization of the heterotrimeric G protein alpha subunit.

The structures of biologically active natural products have long served as inspiration in drug discovery. This Perspective outlines design principles and connectivity patterns for the de novo combination of natural product-derived fragments. The resulting ‘pseudo-natural products’ retain biological relevance yet exhibit structures and bioactivities not found in the natural products and their derivatives.

The European Lead Factory combines assets and experience from major pharma with innovation and agility of academia and SMEs in a collaborative platform to expand access to high-throughput screening. With many successes heading towards the clinic, the organization is broadening its approach to screening and partnering.

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 localization or protein interactions provides new optimism in this field.

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.