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1.
J Med Chem ; 67(4): 3039-3065, 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38306405

RESUMEN

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Apoptosis , Conformación Molecular , ADN , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química
2.
J Med Chem ; 67(2): 864-884, 2024 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-38197367

RESUMEN

The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes. This Perspective is our attempt to analyze reports of DEL screening with the purpose of providing a rigorous and useful account of the binding modes observed for DEL-derived ligands with a focus on binding mode novelty.


Asunto(s)
ADN , Bibliotecas de Moléculas Pequeñas , Bibliotecas de Moléculas Pequeñas/química , Ligandos , ADN/química , Descubrimiento de Drogas , Técnicas Químicas Combinatorias
3.
J Med Chem ; 66(23): 16051-16061, 2023 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-37996079

RESUMEN

WD40 repeat-containing protein 91 (WDR91) regulates early-to-late endosome conversion and plays vital roles in endosome fusion, recycling, and transport. WDR91 was recently identified as a potential host factor for viral infection. We employed DNA-encoded chemical library (DEL) selection against the WDR domain of WDR91, followed by machine learning to predict ligands from the synthetically accessible Enamine REAL database. Screening of predicted compounds identified a WDR91 selective compound 1, with a KD of 6 ± 2 µM by surface plasmon resonance. The co-crystal structure confirmed the binding of 1 to the WDR91 side pocket, in proximity to cysteine 487, which led to the discovery of covalent analogues 18 and 19. The covalent adduct formation for 18 and 19 was confirmed by intact mass liquid chromatography-mass spectrometry. The discovery of 1, 18, and 19, accompanying structure-activity relationship, and the co-crystal structures provide valuable insights for designing potent and selective chemical tools against WDR91 to evaluate its therapeutic potential.


Asunto(s)
ADN , Bibliotecas de Moléculas Pequeñas , ADN/química , Biblioteca de Genes , Ligandos , Aprendizaje Automático , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química
4.
J Med Chem ; 64(19): 14377-14425, 2021 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-34569791

RESUMEN

This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 µg/mL). Lack of activity against E. coli was maintained (IC50 > 20 µM and MIC > 128 µg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.


Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Antibacterianos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/química , Cristalografía por Rayos X , Farmacorresistencia Bacteriana/efectos de los fármacos , Inhibidores Enzimáticos/química , Escherichia coli/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad
5.
Bioorg Med Chem ; 42: 116223, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34091303

RESUMEN

Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton's Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The epoxide BTK inhibitors described here are the first ever reported to utilize this electrophile for this target.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , ADN/química , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Agammaglobulinemia Tirosina Quinasa/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
6.
J Med Chem ; 64(10): 6730-6744, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-33955740

RESUMEN

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.


Asunto(s)
Oxidorreductasas de Alcohol/antagonistas & inhibidores , ADN/química , Bibliotecas de Moléculas Pequeñas/química , Oxidorreductasas de Alcohol/metabolismo , Animales , Sitios de Unión , Cristalografía por Rayos X , ADN/metabolismo , Diseño de Fármacos , Semivida , Humanos , Hiperoxaluria Primaria/metabolismo , Hiperoxaluria Primaria/patología , Indoles/química , Indoles/metabolismo , Masculino , Ratones , Simulación del Acoplamiento Molecular , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/metabolismo , Transaminasas/genética , Transaminasas/metabolismo
7.
Bioorg Med Chem ; 41: 116216, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34023664

RESUMEN

Inhibition of soluble epoxide hydrolase (sEH) has recently emerged as a new approach to treat cardiovascular disease and respiratory disease. Inhibitors based on 1,3,5-triazine chemotype were discovered through affinity selection against two triazine-based DNA-encoded libraries. The structure and activity relationship study led to the expansion of the original 1,4-cycloalkyl series to related aniline, piperidine, quinoline, aryl-ether and benzylic series. The 1,3-cycloalkyl chemotype led to the discovery of a clinical candidate (GSK2256294) for COPD.


Asunto(s)
Ciclohexilaminas/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Triazinas/farmacología , Ciclohexilaminas/química , Descubrimiento de Drogas , Humanos , Estructura Molecular , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas , Triazinas/química
8.
J Med Chem ; 64(8): 5049-5066, 2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33844532

RESUMEN

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.


Asunto(s)
ADN/química , Receptor alfa de Estrógeno/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Química Clic , ADN/metabolismo , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/genética , Femenino , Semivida , Humanos , Indoles/química , Indoles/metabolismo , Cinética , Ratones , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Med Chem ; 64(6): 3165-3184, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33683117

RESUMEN

Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa c-Mer/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Minería de Datos , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Tirosina Quinasa c-Mer/química , Tirosina Quinasa c-Mer/metabolismo
10.
J Med Chem ; 63(14): 7840-7856, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32584034

RESUMEN

The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.


Asunto(s)
Hidantoínas/uso terapéutico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Piperidinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Animales , Bleomicina , Cristalografía por Rayos X , ADN/química , Perros , Humanos , Hidantoínas/síntesis química , Hidantoínas/metabolismo , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/metabolismo , Piperidinas/síntesis química , Piperidinas/metabolismo , Unión Proteica , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/metabolismo
11.
J Med Chem ; 63(16): 8857-8866, 2020 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-32525674

RESUMEN

DNA-encoded small molecule libraries (DELs) have enabled discovery of novel inhibitors for many distinct protein targets of therapeutic value. We demonstrate a new approach applying machine learning to DEL selection data by identifying active molecules from large libraries of commercial and easily synthesizable compounds. We train models using only DEL selection data and apply automated or automatable filters to the predictions. We perform a large prospective study (∼2000 compounds) across three diverse protein targets: sEH (a hydrolase), ERα (a nuclear receptor), and c-KIT (a kinase). The approach is effective, with an overall hit rate of ∼30% at 30 µM and discovery of potent compounds (IC50 < 10 nM) for every target. The system makes useful predictions even for molecules dissimilar to the original DEL, and the compounds identified are diverse, predominantly drug-like, and different from known ligands. This work demonstrates a powerful new approach to hit-finding.


Asunto(s)
ADN/química , Descubrimiento de Drogas/métodos , Redes Neurales de la Computación , Bibliotecas de Moléculas Pequeñas/química , Epóxido Hidrolasas/antagonistas & inhibidores , Receptor alfa de Estrógeno/antagonistas & inhibidores , Ligandos , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores
12.
Biochem Pharmacol ; 177: 113939, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32229099

RESUMEN

Aberrant cell cycle activation is a hallmark of carcinogenesis. Recently three cell cycle targeting cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for the treatment of metastatic breast cancer. CDK4/6 inhibitors suppress proliferation through inhibition of CDK4/6-dependent retinoblastoma-1 (Rb1) phosphorylation and inactivation, a key regulatory step in G1-to-S-phase transition. Importantly, aberrant cell cycle activation is also linked with several non-oncological diseases including acute kidney injury (AKI). AKI is a common disorder caused by toxic, inflammatory, and ischemic damage to renal tubular epithelial cells (RTECs). Interestingly, AKI triggered by the anti-cancer drug cisplatin can be mitigated by ribociclib, a CDK4/6 inhibitor, through mechanisms that remain unclear. Employing in vivo cell cycle analysis and functional Rb1 knock-down, here, we have examined the cellular and pharmacological basis of the renal protective effects of ribociclib during cisplatin nephrotoxicity. Remarkably, siRNA-mediated Rb1 silencing or RTEC-specific Rb1 gene ablation did not alter the severity of cisplatin-associated AKI; however, it completely abrogated the protective effects conferred by ribociclib administration. Furthermore, we find that cisplatin treatment evokes CDK4/6 activation and Rb1 phosphorylation in the normally quiescent RTECs, however, this is not followed by S-phase entry likely due to DNA-damage induced G1 arrest. The cytoprotective effects of ribociclib are thus not a result of suppression of S-phase entry but are likely dependent on the maintenance of Rb1 in a hypo-phosphorylated and functionally active form under stress conditions. These findings delineate the role of Rb1 in AKI and illustrate the pharmacological basis of the renal protective effects of CDK4/6 inhibitors.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Aminopiridinas/uso terapéutico , Cisplatino/farmacología , Sustancias Protectoras/uso terapéutico , Purinas/uso terapéutico , Proteínas de Unión a Retinoblastoma/metabolismo , Lesión Renal Aguda/metabolismo , Aminopiridinas/farmacología , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Células Cultivadas , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Citoprotección , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Técnicas de Silenciamiento del Gen , Túbulos Renales/patología , Masculino , Ratones , Ratones Noqueados , Fosforilación/efectos de los fármacos , Sustancias Protectoras/farmacología , Purinas/farmacología , Proteínas de Unión a Retinoblastoma/genética , Transducción de Señal/efectos de los fármacos
13.
Molecules ; 24(10)2019 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-31137911

RESUMEN

Inspired by the many reported successful applications of DNA-encoded chemical libraries in drug discovery projects with protein targets, we decided to apply this platform to nucleic acid targets. We used a 120-billion-compound set of 33 distinct DNA-encoded chemical libraries and affinity-mediated selection to discover binders to a panel of DNA targets. Here, we report the successful discovery of small molecules that specifically interacted with DNA G-quartets, which are stable structural motifs found in G-rich regions of genomic DNA, including in the promoter regions of oncogenes. For this study, we chose the G-quartet sequence found in the c-myc promoter as a primary target. Compounds enriched using affinity-mediated selection against this target demonstrated high-affinity binding and high specificity over DNA sequences not containing G-quartet motifs. These compounds demonstrated a moderate ability to discriminate between different G-quartet motifs and also demonstrated activity in a cell-based assay, suggesting direct target engagement in the cell. DNA-encoded chemical libraries and affinity-mediated selection are uniquely suited to discover binders to targets that have no inherent activity outside of a cellular context, and they may also be of utility in other nucleic acid structural motifs.


Asunto(s)
ADN/química , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas , Línea Celular Tumoral , Supervivencia Celular , Humanos , Resonancia por Plasmón de Superficie
14.
ACS Comb Sci ; 20(5): 251-255, 2018 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-29648439

RESUMEN

Encoded library technology (ELT) is an effective approach to the discovery of novel small-molecule ligands for biological targets. A key factor for the success of the technology is the chemical diversity of the libraries. Here we report the development of DNA-conjugated benzimidazoles. Using 4-fluoro-3-nitrobenzoic acid as a key synthon, we synthesized a 320 million-member DNA-encoded benzimidazole library using Fmoc-protected amino acids, amines and aldehydes as diversity elements. Affinity selection of the library led to the discovery of a novel, potent and specific antagonist of the NK3 receptor.


Asunto(s)
Bencimidazoles/síntesis química , ADN/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Aminoácidos/química , Bencimidazoles/química , Concentración de Iones de Hidrógeno , Nitrobenzoatos/química , Bibliotecas de Moléculas Pequeñas/química
15.
SLAS Discov ; 23(5): 429-436, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29316408

RESUMEN

The discovery of ligands via affinity-mediated selection of DNA-encoded chemical libraries is driven by the quality and concentration of the protein target. G-protein-coupled receptors (GPCRs) and other membrane-bound targets can be difficult to isolate in their functional state and at high concentrations, and therefore have been challenging for affinity-mediated selection. Here, we report a successful selection campaign against protease-activated receptor 2 (PAR2). Using a thermo-stabilized mutant of PAR2, we conducted affinity selection using our >100-billion-compound DNA-encoded library. We observed a number of putative ligands enriched upon selection, and subsequent cellular profiling revealed these ligands to comprise both agonists and antagonists. The agonist series shared structural similarity with known agonists. The antagonists were shown to bind in a novel allosteric binding site on the PAR2 protein. This report serves to demonstrate that cell-free affinity selection against GPCRs can be achieved with mutant stabilized protein targets.


Asunto(s)
ADN/genética , Mutación/efectos de los fármacos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Sitio Alostérico/efectos de los fármacos , Línea Celular , Células HEK293 , Humanos , Ligandos , Proteínas/genética , Receptor PAR-2 , Receptores Acoplados a Proteínas G/genética
18.
ACS Chem Biol ; 12(11): 2730-2736, 2017 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-29043777

RESUMEN

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/antagonistas & inhibidores , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Sondas Moleculares/química , Sondas Moleculares/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacos , ATPasas Asociadas con Actividades Celulares Diversas/química , Línea Celular Tumoral , Cromatina/metabolismo , Proteínas de Unión al ADN/química , Descubrimiento de Drogas , Histonas/metabolismo , Humanos , Ligandos , Modelos Moleculares , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo
19.
ACS Med Chem Lett ; 8(2): 239-244, 2017 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-28197319

RESUMEN

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 µM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a ß-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 µM and Bcl-xL at >99 µM, and induces cleaved caspase-3 in MV4-11 cells with an IC50 of 3 µM after 6 h.

20.
Chembiochem ; 18(9): 864-871, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28056160

RESUMEN

We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets.


Asunto(s)
ADN/química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Agammaglobulinemia Tirosina Quinasa , Sitios de Unión , Línea Celular , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , ADN/metabolismo , Humanos , Cinética , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo
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