Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
1.
Nat Chem Biol ; 20(2): 170-179, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37919549

RESUMEN

Small molecules that induce protein-protein associations represent powerful tools to modulate cell circuitry. We sought to develop a platform for the direct discovery of compounds able to induce association of any two preselected proteins, using the E3 ligase von Hippel-Lindau (VHL) and bromodomains as test systems. Leveraging the screening power of DNA-encoded libraries (DELs), we synthesized ~1 million DNA-encoded compounds that possess a VHL-targeting ligand, a variety of connectors and a diversity element generated by split-and-pool combinatorial chemistry. By screening our DEL against bromodomains in the presence and absence of VHL, we could identify VHL-bound molecules that simultaneously bind bromodomains. For highly barcode-enriched library members, ternary complex formation leading to bromodomain degradation was confirmed in cells. Furthermore, a ternary complex crystal structure was obtained for our most enriched library member with BRD4BD1 and a VHL complex. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.


Asunto(s)
Proteínas Nucleares , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/química , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción , Ubiquitina-Proteína Ligasas/metabolismo , ADN
2.
J Am Chem Soc ; 145(42): 23281-23291, 2023 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-37816014

RESUMEN

The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding toward one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, which constitute a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence or absence of a presenter protein, using the "presenter ratio", the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity. Through this approach, we identified a range of cooperative, noncooperative, and uncooperative compounds in a single DNA-encoded library screen with bromodomain containing protein (BRD)9 and the VHL-elongin C-elongin B (VCB) complex. Our most cooperative hit compound, 13-7, exhibits micromolar binding affinity to BRD9 but nanomolar affinity for the ternary complex with BRD9 and VCB, with cooperativity comparable to classical molecular glues. This approach may enable the rational discovery of molecular glues for preselected proteins and thus facilitate the transition to a new paradigm of small-molecule therapeutics.


Asunto(s)
ADN , Proteínas , Sitios de Unión , Dominios Proteicos
3.
Angew Chem Int Ed Engl ; 61(38): e202203221, 2022 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-35395129

RESUMEN

Cyclopropane-fused N-heterocycles are featured in various biologically active compounds and represent attractive scaffolds in medicinal chemistry. However, synthesis routes to access structurally and functionally diverse cyclopropane-fused N-heterocycles remain underexplored. Leveraging novel α-diazo acylating agents, we report a general approach for the direct and modular synthesis of cyclopropane-fused lactams from unsaturated amines. The operationally simple transformation, which proceeds through successive acylation, (3+2) cycloaddition and fragmentation, tolerates a broad range of functional groups and yields a wide spectrum of complex molecular scaffolds, including fused, bridged and spiro ring systems. We demonstrate the utility of this transformation in the concise syntheses of therapeutic agents milnaciprane and amitifadine.


Asunto(s)
Aminas , Ciclopropanos , Aminas/química , Reacción de Cicloadición , Ciclopropanos/química , Indicadores y Reactivos , Lactamas
4.
J Am Chem Soc ; 142(17): 7776-7782, 2020 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-32267148

RESUMEN

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles, and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features, related to elements found to be powerful in phenotypic screening.


Asunto(s)
Alcadienos/química , Reacción de Cicloadición/métodos , Biblioteca de Genes , Oligonucleótidos/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Humanos
5.
Bioorg Med Chem Lett ; 24(20): 4871-5, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25241924

RESUMEN

This Letter describes methodology to enable the identification of tool or therapeutic lipopeptides which modulate the function of membrane bound proteins. The choice of lipopeptides as a chemotype is the amalgamation of multiple medicinal chemistry considerations including duration of action, low systemic exposure and access to intracellular components. The 'lipopeptide shuffle' has been applied here to the APJ receptor and has rapidly resulted in the discovery of a 33 nM APJ agonist hit from an initial 369 member lipopeptide synthetic array.


Asunto(s)
Diseño de Fármacos , Lipopéptidos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Receptores de Apelina , Relación Dosis-Respuesta a Droga , Humanos , Lipopéptidos/química , Lipopéptidos/genética , Conformación Molecular , Relación Estructura-Actividad
6.
bioRxiv ; 2023 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-37292909

RESUMEN

The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading to the formation of a ternary complex, despite weaker binding towards one or both individual proteins. Notably, the extent of cooperativity distinguishes molecular glues from bifunctional compounds, a second class of inducers of protein-protein interactions. However, apart from serendipitous discovery, there have been limited rational screening strategies for the high cooperativity exhibited by molecular glues. Here, we propose a binding-based screen of DNA-barcoded compounds on a target protein in the presence and absence of a presenter protein, using the "presenter ratio", the ratio of ternary enrichment to binary enrichment, as a predictive measure of cooperativity. Through this approach, we identified a range of cooperative, noncooperative, and uncooperative compounds in a single DNA-encoded library screen with bromodomain (BRD)9 and the VHL-elongin C-elongin B (VCB) complex. Our most cooperative hit compound, 13-7 , exhibits micromolar binding affinity to BRD9 but nanomolar affinity for the ternary complex with BRD9 and VCB, with cooperativity comparable to classical molecular glues. This approach may enable the discovery of molecular glues for pre-selected proteins and thus facilitate the transition to a new paradigm of molecular therapeutics.

7.
Nat Commun ; 14(1): 4930, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37582753

RESUMEN

Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.


Asunto(s)
Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas , Bibliotecas de Moléculas Pequeñas/química , Descubrimiento de Drogas/métodos , Biblioteca de Genes , ADN/genética , ADN/química
8.
Cell Chem Biol ; 30(3): 235-247.e12, 2023 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-36863346

RESUMEN

Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.


Asunto(s)
Neoplasias , Factores de Transcripción , Animales , Humanos , Ratones , Factor de Transcripción Ikaros , Inmunoterapia , Neoplasias/terapia , Neoplasias/metabolismo , Linfocitos T Reguladores/metabolismo , Factores de Transcripción/metabolismo
9.
J Med Chem ; 65(24): 16173-16203, 2022 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-36399068

RESUMEN

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).


Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Diseño de Fármacos , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pirazoles/farmacología , Pirazoles/uso terapéutico
10.
Bioorg Med Chem Lett ; 20(1): 35-7, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19954976

RESUMEN

High throughput screening and hit to lead optimization led to the identification of 'carene' as a promising scaffold showing selective S1P(1) receptor agonism. In parallel to this work we have established a pharmacophore model for the S1P(1) receptor highlighting the minimal structural requirement necessary for potent receptor agonism.


Asunto(s)
Monoterpenos/química , Pirazoles/química , Receptores de Lisoesfingolípidos/agonistas , Monoterpenos Bicíclicos , Ensayos Analíticos de Alto Rendimiento , Enlace de Hidrógeno , Pirazoles/síntesis química , Pirazoles/farmacología , Receptores de Lisoesfingolípidos/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
12.
ChemMedChem ; 12(5): 358-361, 2017 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-28181424

RESUMEN

The first examples of biologically active monocyclic 1,2-azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison with their corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research.


Asunto(s)
Compuestos de Boro/química , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Administración Oral , Animales , Sitios de Unión , Compuestos de Boro/metabolismo , Compuestos de Boro/farmacocinética , Química Farmacéutica , Quinasa 2 Dependiente de la Ciclina/metabolismo , Semivida , Enlace de Hidrógeno , Masculino , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Solubilidad
13.
Curr Opin Chem Biol ; 32: 60-6, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27258401

RESUMEN

Multiple sclerosis is a devastating chronic autoimmune disease affecting women and men of all ages. Inflammation of the central nervous system causes demyelination and ultimately neuropsychological dysfunction. Myriocin, a natural product with strong immunosuppressant activity was interrogated leading to a new class of immunomodulator with a unique mode of action. In this review, we will summarize these findings, the mechanism hypothesis and discuss the data's ultimately leading to the approval of Gilenya™ as the first oral treatment for multiple sclerosis.


Asunto(s)
Productos Biológicos/uso terapéutico , Clorhidrato de Fingolimod/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Administración Oral , Animales , Productos Biológicos/administración & dosificación , Humanos
15.
J Am Chem Soc ; 127(31): 11159-75, 2005 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-16076224

RESUMEN

The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic, is described. After a brief introduction to the target molecule and its structural motifs, it is shown that retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactions that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under conditions that avoided the initially encountered destructive ring contraction process.


Asunto(s)
Antibacterianos/síntesis química , Tioestreptona/síntesis química , Antibacterianos/química , Dimerización , Estereoisomerismo , Tioestreptona/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA