RESUMEN
Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a kinact/KI of 4600 M-1 s-1, shows <1 µM caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising in vivo profile.
RESUMEN
PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.
Asunto(s)
Inhibidores Enzimáticos , Proteína-Arginina N-Metiltransferasas , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/metabolismo , Humanos , Animales , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Ratones , Descubrimiento de Drogas , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis químicaRESUMEN
Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.
Asunto(s)
Cisteína , Diseño de Fármacos , Bibliotecas de Moléculas Pequeñas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Cristalografía por Rayos X , Cisteína/química , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Relación Estructura-Actividad , Modelos Moleculares , Antígenos de Histocompatibilidad MenorRESUMEN
Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.
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Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.
Asunto(s)
Receptores ErbB , Exones , Inhibidores de Proteínas Quinasas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Animales , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , Línea Celular Tumoral , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Mutagénesis Insercional , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Antitumor por Modelo de Xenoinjerto , MutaciónRESUMEN
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Neoplasias , Animales , Humanos , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias/tratamiento farmacológico , Diseño de Fármacos , Glicina/uso terapéutico , Mutación , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas de Unión al ADN/antagonistas & inhibidores , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Modelos Moleculares , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Especificidad por Sustrato , Ensayo de Tumor de Célula MadreRESUMEN
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.
Asunto(s)
Antineoplásicos/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Compuestos Organofosforados/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones Desnudos , Ratones SCID , Mutación , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The facile synthesis of both saturated and unsaturated tricyclic pyrrolo-pyridones starting from a single readily available, common monocyclic reagent has been developed. An intermolecular annulation via a tandem Buchwald-Hartwig/Heck reaction led to the synthesis of ß-carbolinones. The analogous semisaturated tricyclic pyrrolo-pyridones were prepared in good to excellent yields by sequential Buchwald-Hartwig and Fischer indole reactions. The methods feature mild reaction conditions and good functional group tolerance.
RESUMEN
Recently we have documented research efforts aimed at new classes of oxetanes as well as spiroheteroalicyclic ring systems (which we have termed 'Compact Modules') designed to expand the palette of tailored module scaffolds available to medicinal chemists, which constitute an important role for synthetic chemistry in the drug discovery process. An essential component for this process is to provide access to specific molecular topologies with functional group diversity, essential for generating leads that discriminate among biological targets, therefore promoting selectivity and enhancing the safety profile of the final clinical candidates.
Asunto(s)
Azetidinas/química , Éteres Cíclicos/química , Compuestos de Espiro/química , Azetidinas/síntesis química , Descubrimiento de Drogas , Éteres Cíclicos/síntesis química , Estructura Molecular , Compuestos de Espiro/síntesis químicaRESUMEN
The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.
Asunto(s)
Compuestos Aza/síntesis química , Heptanos/síntesis química , Compuestos de Espiro/síntesis química , Éteres Cíclicos/química , Modelos Moleculares , Estructura MolecularRESUMEN
The syntheses of a variety of novel angular azaspiro[3.3]heptanes are reported. gem-Difluoro and gem-dimethyl variants of the angular 1,6-diazaspiro[3.3]heptane module were prepared in high yields using efficient sequences. Additionally, a practical one-pot synthesis of 5-oxo-2-azaspiro[3.3]heptanes and subsequent conversions into functionalized derivatives are described. The methods reported are amenable to the synthesis of these building blocks for drug discovery as members of a library or individually on a preparative scale.
Asunto(s)
Azetidinas/síntesis química , Heptanos/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Azetidinas/química , Heptanos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes is disclosed. These spirocyclic systems may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insufficiently stable to allow their use in drug discovery. Conformational details are discussed on the basis of X-ray crystallographic structures.
Asunto(s)
Heptanos/síntesis química , Cristalografía por Rayos X , Heptanos/química , Modelos Moleculares , Estructura MolecularRESUMEN
Tandem carbenoid generation, ylide formation and [2,3]-rearrangement is a powerful method for the construction of bicyclic and linearly fused tricyclic systems containing a seven-membered ring.
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Compuestos Macrocíclicos/síntesis química , Metano/análogos & derivados , Oxígeno/química , Productos Biológicos/química , Hidrocarburos/química , Compuestos Macrocíclicos/química , Metano/química , Estructura Molecular , Factores de TiempoRESUMEN
The regioselective head-to-head [2 + 2] cyclodimerization of allenyl boronate catalyzed by the ruthenium catalyst [Cp*RuCl(COD)] leads to a novel diboronated 1,3-dimethylenecyclobutane. Consecutive palladium-catalyzed C-C couplings open a route to novel disubstituted 1,3-dimethylenecyclobutane species. The X-ray crystalline structure of the phenyl-substituted 1,3-dimethylenecyclobutane is provided.