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1.
Nat Chem Biol ; 20(1): 93-102, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37679459

RESUMEN

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. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.


Asunto(s)
Ciclinas , Ubiquitina-Proteína Ligasas , Ciclinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteolisis , Relación Estructura-Actividad
2.
Nature ; 585(7824): 293-297, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32494016

RESUMEN

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3-5, we identify CR8-a cyclin-dependent kinase (CDK) inhibitor6-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.


Asunto(s)
Ciclinas/deficiencia , Ciclinas/metabolismo , Proteolisis/efectos de los fármacos , Purinas/química , Purinas/farmacología , Piridinas/química , Piridinas/farmacología , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/química , Proteínas de Unión al ADN/metabolismo , Humanos , Modelos Moleculares , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica/efectos de los fármacos , Purinas/toxicidad , Piridinas/toxicidad , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Ubiquitinación/efectos de los fármacos
3.
J Am Chem Soc ; 145(38): 20874-20882, 2023 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-37704585

RESUMEN

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. The polyA tail is also a convenient handle to enrich binders with magnetic poly(dT)25 beads before sequencing. In a benchmarking system, we show that ligands spanning nanomolar to double-digit micromolar binding can be cleanly identified by TdT extension, whereas only the tightest binding ligands are identified by classical affinity selection. The method is simple to implement and can function on any DEL that bears a free 3'-end.


Asunto(s)
ADN Nucleotidilexotransferasa , ADN Polimerasa Dirigida por ADN , ADN Nucleotidilexotransferasa/química , ADN Nucleotidilexotransferasa/genética , ADN Nucleotidilexotransferasa/metabolismo , ADN Polimerasa Dirigida por ADN/química , ADN/química , Nucleótidos , Colorantes
4.
Chembiochem ; 24(8): e202300093, 2023 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-36942862

RESUMEN

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. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie.


Asunto(s)
Biología , Humanos , Paris
5.
Chembiochem ; 22(19): 2823-2825, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34347337

RESUMEN

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. Medicinal chemistry is the design, synthesis, and optimization of biologically active molecules aimed at discovering new drug candidates - a mission that in many ways overlaps with the scope of chemical biology. Chemical biology is by now a mature field of science for which a more precise definition of what it encompasses, in the frame of EFMC, is timely. This article discusses chemical biology as currently understood by EFMC, including all activities dealing with the design and synthesis of biologically active chemical tools and their use to probe, characterize, or influence biological systems.


Asunto(s)
Preparaciones Farmacéuticas/química , Química Farmacéutica , Europa (Continente) , Humanos , Preparaciones Farmacéuticas/síntesis química
6.
Bioorg Med Chem ; 52: 116508, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34800876

RESUMEN

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. These measures read signal quantity and overall integrity, but do not report on specific damages in the encoded information. Herein, we use next generation sequencing (NGS) to measure the quality of the read signal in order to quantify the truthfulness of the retrieved information. We identify CuAAC to be the worst offender in terms of DNA damage amongst commonly used reactions in DELs, causing an increase of G â†’ T transversions. Furthermore, we show that the analysis provides useful information even in fully elaborated DELs; indeed we see that vestiges of the synthetic history, both chemical and biochemical, are written into the mutational spectra of NGS datasets.


Asunto(s)
ADN/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , ADN/genética , Biblioteca de Genes , Estructura Molecular , Mutación , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química
7.
Chemistry ; 26(66): 15298-15312, 2020 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-32852800

RESUMEN

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(sp3 )-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. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3 )-H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (-)-epicoccin G and to the more challenging (-)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (-)-epicoccin G and (-)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.


Asunto(s)
Productos Biológicos , Piperazinas/síntesis química , Oxidación-Reducción , Piperazinas/química , Estereoisomerismo
8.
Phys Chem Chem Phys ; 22(24): 13431-13439, 2020 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-32515452

RESUMEN

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. A low- and high-level quantum-chemistry-based screening of more than one hundred dienes identified 2,3-dibromobutadiene (DBB) as an optimal candidate for efficient separation of its gauche and s-trans conformers by electrostatic deflection. A preparation method for DBB was developed which enabled the generation of dense molecular beams of this compound. The theoretical predictions of the molecular properties of DBB were validated by the successful separation of the conformers in the molecular beam. A marked difference in photofragment ion yields of the two conformers upon femtosecond-laser pulse ionization was observed, pointing at a pronounced conformer-specific fragmentation dynamics of ionized DBB. Our work sets the stage for a rigorous examination of mechanistic models of cycloaddition reactions under controlled conditions in the gas phase.

9.
Chimia (Aarau) ; 74(9): 693-698, 2020 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-32958106

RESUMEN

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. Hence, although new alkylating motifs are unlikely to progress through the clinic, the legacy of these medicines is that we now understand the therapeutic potential of targeting DNA damage repair pathways. Here we look at the history of alkylating agents as anticancer drugs, while also summarizing the different mechanistic approaches to covalent DNA modification. We also provide several case studies on how insights into compromised DNA repair pathways are paving the way for potent and less toxic targeted medicines against the DNA damage response.


Asunto(s)
Antineoplásicos , Neoplasias , Alquilantes/uso terapéutico , Antineoplásicos/farmacología , ADN , Daño del ADN , Reparación del ADN , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética
10.
Angew Chem Int Ed Engl ; 58(28): 9570-9574, 2019 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-30938482

RESUMEN

Here we show a seven-step chemical synthesis of a DNA-encoded macrocycle library (DEML) on DNA. Inspired by polyketide and mixed peptide-polyketide natural products, the library was designed to incorporate rich backbone diversity. Achieving this diversity, however, comes at the cost of the custom synthesis of bifunctional building block libraries. This study outlines the importance of careful retrosynthetic design in DNA-encoded libraries, while revealing areas where new DNA synthetic methods are needed.


Asunto(s)
Compuestos Macrocíclicos/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Humanos
11.
Angew Chem Int Ed Engl ; 58(25): 8432-8436, 2019 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-31021463

RESUMEN

O6 -carboxymethylguanine (O6 -CMG) is a highly mutagenic alkylation product of DNA, triggering transition mutations relevant to gastrointestinal cancer. However, precise localization of a single O6 -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 O6 -CMG. A unique O6 -CMG signal was observed during NPS and a single-event call accuracy of >95 % was achieved. Moreover, O6 -CMG was found to be a replication obstacle for Phi29 DNA polymerase (Phi29 DNAP), suggesting this lesion could cause DNA sequencing biases in next generation sequencing (NGS) approaches.


Asunto(s)
ADN Polimerasa Dirigida por ADN/genética , ADN/genética , Guanina/química , ADN/química , ADN Polimerasa Dirigida por ADN/metabolismo , Guanina/análogos & derivados , Humanos , Estructura Molecular , Secuenciación de Nanoporos
12.
Chembiochem ; 19(15): 1638-1642, 2018 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-29732707

RESUMEN

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. Next-generation sequencing (NGS) is ideally suited for the broad characterization of sequence or structure selectivities because it analyzes many sequences at once. Herein, NGS is used to report on the chemoselectivity of alkylating agents on RNA and this technology is applied to the previously uncharacterized alkylating agent trimethylsilyl diazomethane.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , ADN/química , Diazometano/análogos & derivados , ARN/química , Compuestos de Trimetilsililo/farmacología , Alquilación/efectos de los fármacos , Antineoplásicos Alquilantes/química , Diazometano/química , Diazometano/farmacología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias/tratamiento farmacológico , Compuestos de Trimetilsililo/química
13.
Chimia (Aarau) ; 72(11): 777-781, 2018 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-30514420

RESUMEN

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. Techniques for direct modification will become more important in the coming years and we give a current snapshot of the field here, with a bias towards our own contributions.


Asunto(s)
ARN Mensajero/química , Técnicas de Síntesis en Fase Sólida/métodos , Transcripción Genética , ARN Mensajero/metabolismo
14.
Chembiochem ; 18(24): 2368-2375, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-28972683

RESUMEN

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. In particular, genomic regions shielded by transcription factors or packed densely in nucleosomes are poorly repaired by nucleotide excision repair and are far more susceptible to mutation. There are plenty of approved therapies, the mode-of-action of which is to alkylate DNA, and although historically efforts have been focused on understanding how chemicals modify DNA, these new findings suggest that focus should be shifted to understanding genome-wide repair specificities when different types of alkylation damage occur.


Asunto(s)
Daño del ADN , Reparación del ADN , Genoma , Alquilación , Animales , Humanos
15.
Chem Soc Rev ; 45(9): 2637-55, 2016 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-26992131

RESUMEN

Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guanine-cytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, π-π stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.


Asunto(s)
ADN/metabolismo , ADN/uso terapéutico , Epigenómica/métodos , Perfilación de la Expresión Génica/métodos , ARN/metabolismo , ARN/uso terapéutico , Animales , ADN/química , ADN/genética , Humanos , ARN/química , ARN/genética
16.
Org Biomol Chem ; 14(32): 7606-9, 2016 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-27424916

RESUMEN

A broad palette of bioconjugation reactions are available for chemical biologists, but an area that still requires investigation is high-rate constant reactions. These are indispensable in certain applications, particularly for in vivo labelling. Appropriately positioned boronic acids accelerate normally sluggish Schiff base condensations of α-effect nucleophiles by five orders of magnitude - providing a new entry to the rare set of reactions that have a rate constant above 100 M(-1) s(-1) under physiological conditions. I summarize here a number of recent reports, including work from my own group, and outline a mechanistic picture that explains the differing behaviour of seemingly similar substrate classes.

17.
Org Biomol Chem ; 14(24): 5529-33, 2016 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-26876694

RESUMEN

We use kinetic data, photophysical properties, and mechanistic analyses to compare recently developed high-rate constant oxime and hydrazone formations. We show that when Schiff base formation between aldehydes and arylhydrazines is carried out with an appropriately positioned boron atom, then aromatic B-N heterocycles form irreversibly. These consist of an extended aromatic structure amenable to the tailoring of specific properties such as reaction rate and fluorescence. The reactions work best in neutral aqueous buffer and can be designed to be fluorogenic - properties which are particularly interesting in bioconjugation.

18.
Chimia (Aarau) ; 75(5): 439-441, 2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-34016240
20.
Chem Soc Rev ; 42(12): 4918-31, 2013 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-23407887

RESUMEN

Catalysed X-H insertion reactions into diazo compounds (where X is any heteroatom) are a powerful yet underutilized class of transformations. The following review will explore the historical development of X-H insertion and give an up-to-date account of the metal catalysts most often employed, including an assessment of their strengths and weaknesses. Despite decades of development, recent work on enantioselective variants, as well as applying catalytic X-H insertion towards problems in chemical biology indicate that this field has ample room for innovation.

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