Correction: A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα.

[This corrects the article DOI: 10.1039/D3SC04629J.].

A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα.

Class I phosphoinositide 3-kinases (PI3Ks) control cellular growth, but are also essential in insulin signaling and glucose homeostasis. Pan-PI3K inhibitors thus generate substantial adverse effects, a reality that has plagued drug development against this target class. We present here evidence that a high affinity binding module with the capacity to target all class I PI3K isoforms can facilitate selective degradation of the most frequently mutated class I isoform, PI3Kα, when incorporated into a cereblon-targeted (CRBN) degrader.

Recording Binding Information Directly into DNA-Encoded Libraries Using Terminal Deoxynucleotidyl Transferase.

Terminal deoxynucleotidyl transferase (TdT) is an unusual DNA polymerase that adds untemplated dNTPs to 3'-ends of DNA. If a target protein is expressed as a TdT fusion and incubated with a DNA-encoded library (DEL) in the presence of dATP, the binders of the target induce proximity between TdT and the DNA, promoting the synthesis of a poly-adenine (polyA) tail. The polyA tail length is proportional to the binding affinity, effectively serving as a stable molecular record of binding events.

Design principles for cyclin K molecular glue degraders.

Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928.

Overlaid Transcriptional and Proteome Analyses Identify Mitotic Kinesins as Important Targets of Arylsulfonamide-Mediated RBM39 Degradation.

Unlabelled: Certain arylsulfonamides (ArSulf) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. However, degradation of a splicing factor introduces complex pleiotropic effects that are difficult to untangle, since, aside from direct protein degradation, downstream transcriptional effects also influence the proteome. By overlaying transcriptional data and proteome datasets, we distinguish transcriptional from direct degradation effects, pinpointing those proteins most impacted by splicing changes.

An Active Member of the EFMC: The Division of Medicinal Chemistry and Chemical Biology of the Swiss Chemical Society.

The Division of Medicinal Chemistry and Chemical Biology (DMCCB) of the Swiss Chemical Society is an active contributor to the dynamics of the Swiss and European scientific communities. Founded in 1987, it pursues its mission to foster relationships among its academic and industrial members, to facilitate exchange by organizing symposia and courses, and to encourage scientific excellence. This article presents the DMCCB and highlights both its offer to the community and its participation in the activities of EFMC, the European Federation for Medicinal chemistry and Chemical biology.

PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase.

This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting.

An assessment of the mutational load caused by various reactions used in DNA encoded libraries.

DNA encoded libraries have become an essential hit-finding tool in early drug discovery. Recent advances in synthetic methods for DNA encoded libraries have expanded the available chemical space, but precisely how each type of chemistry affects the DNA is unstudied. Available assays to quantify the damage are limited to write efficiency, where the ability to ligate DNA onto a working encoded library strand is measured, or qPCR is performed to measure the amplifiability of the DNA.

Building Boron Heterocycles into DNA-Encoded Libraries.

DNA-encoded library (DEL) technology uses DNA tags to track the synthetic history of individual members in a split-and-pool combinatorial synthesis scheme. DEL synthesis hinges on robust methodologies that tolerate combinatorial synthesis schemes while not destroying the information in DNA. We introduce here a DEL-compatible reaction that assembles a boron-containing pyridazine heterocycle.

The Chemical Biology-Medicinal Chemistry Continuum: EFMC's Vision.

The European Federation for Medicinal chemistry and Chemical biology (EFMC) is a federation of learned societies. It groups organizations of European scientists working in a dynamic field spanning chemical biology and medicinal chemistry. New ideas, tools, and technologies emerging from a wide array of scientific disciplines continuously energize this rapidly evolving area.

DNA Damaging Agents in Chemical Biology and Cancer.

Despite their toxicity, DNA alkylating drugs remain a cornerstone of anticancer therapy. The classical thinking was that rapidly dividing tumour cells left more of its DNA in an exposed single-stranded state, making these rapidly dividing cells more susceptible to alkylating drugs. As our understanding of DNA repair pathways has matured it is becoming clear that compromised DNA repair - a hallmark of cancer - plays a role as well in defining the therapeutic window of these toxic drugs.

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp )-H Activation Strategy.

This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (-)-epicoccin G and (-)-rostratin A using a double C(sp )-H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8' alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate.

Quantum-chemistry-aided identification, synthesis and experimental validation of model systems for conformationally controlled reaction studies: separation of the conformers of 2,3-dibromobuta-1,3-diene in the gas phase.

The Diels-Alder cycloaddition, in which a diene reacts with a dienophile to form a cyclic compound, counts among the most important tools in organic synthesis. Achieving a precise understanding of its mechanistic details on the quantum level requires new experimental and theoretical methods. Here, we present an experimental approach that separates different diene conformers in a molecular beam as a prerequisite for the investigation of their individual cycloaddition reaction kinetics and dynamics under single-collision conditions in the gas phase.

The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K.

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously.

Nanopore Sequencing Accurately Identifies the Mutagenic DNA Lesion O -Carboxymethyl Guanine and Reveals Its Behavior in Replication.

O -carboxymethylguanine (O -CMG) is a highly mutagenic alkylation product of DNA, triggering transition mutations relevant to gastrointestinal cancer. However, precise localization of a single O -CMG with conventional sequencing platforms is challenging. Here nanopore sequencing (NPS), which directly senses single DNA bases according to their physiochemical properties, was employed to detect O -CMG.

High Sensitivity of Human Translesion DNA Synthesis Polymerase κ to Variation in O-Carboxymethylguanine Structures.

Carboxymethylation of DNA, including the formation of the DNA adduct O-carboxymethylguanine ( O-CMG), is associated with lifestyle factors, such as diet. It can impede replicative polymerases (Pols) and lead to replication fork stalling, or an alternative means for replication to proceed by translesion DNA synthesis (TLS). TLS requires specialized DNA Pols characterized by open and preformed active sites capable of preferential bypass of alkylated DNA adducts but that have high error rates, leading to mutations.

Direct and Selective Modification of RNA - An Open Challenge in Nucleic Acid Chemistry.

We present the state-of-the-art in direct RNA modification as well as the challenges that hold back further development of RNA mechanistic probes and medicines. Solid-phase synthesis has revolutionized the synthesis of short DNAs and RNAs. Many open questions in RNA biology are with large long-non-coding RNAs or mRNAs and there is also interest in developing these big RNAs as medicines.

A new water soluble copper N-heterocyclic carbene complex delivers mild OG-selective RNA alkylation.

We show here that copper carbenes generated from diazo acetamides alkylate single RNAs, mRNAs, or pools of total transcriptome RNA, delivering exclusively alkylation at the O6 position in guanine (O6G). Although the reaction is effective with free copper some RNA fragmentation occurs, a problem we resolve by developing a novel water-stable copper N-heterocyclic carbene complex. Carboxymethyl adducts at O6G are known mutagenic lesions in DNA but their relevance in RNA biochemistry is unknown.

Profiling the Nucleobase and Structure Selectivity of Anticancer Drugs and other DNA Alkylating Agents by RNA Sequencing.

Drugs that covalently modify DNA are components of most chemotherapy regimens, often serving as first-line treatments. Classically, the reactivity and selectivity of DNA alkylating agents has been determined in vitro with short oligonucleotides. A statistically sound analysis of sequence preferences of alkylating agents is untenable with serial analysis methods because of the combinatorial explosion of sequence possibilities.

Genomic Studies Reveal New Aspects of the Biology of DNA Damaging Agents.

A flurry of papers has appeared recently to force a rethinking of our understanding of how chemicals, light, and metal complexes damage our genomes. Conventional wisdom was that damaging agents were indiscriminate and it was statistical bad luck, coupled with evolutionary selection, that drove mutational signatures after exposure of DNA to damaging agents. Recent data, however, suggests that primary DNA damage itself does not drive mutational signatures; instead, it is the selectivity of repair pathways on different regions of the genome that is decisive.

Copper carbenes alkylate guanine chemoselectively through a substrate directed reaction.

Cu(i) carbenes derived from α-diazocarbonyl compounds lead to selective alkylation of the O position in guanine (O-G) in mono- and oligonucleotides. Only purine-type lactam oxygens are targeted - other types of amides or lactams are poorly reactive under conditions that give smooth alkylation of guanine. Mechanistic studies point to N7G as a directing group that controls selectivity.