RESUMEN
Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.
Asunto(s)
Péptidos Cíclicos , Proteínas Proto-Oncogénicas p21(ras) , ARN Mensajero , Relación Estructura-Actividad , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacocinética , Humanos , ARN Mensajero/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Estructura Molecular , Animales , Relación Dosis-Respuesta a DrogaRESUMEN
Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.
Asunto(s)
Péptidos , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Células CACO-2 , Péptidos/farmacología , Péptidos/metabolismo , Péptidos Cíclicos/química , Conformación MolecularRESUMEN
Metrological traceability is essential to ensure the reliability of calibration tests. Calibration certificates usually include information on only one upper-level reference standard. As metrological traceability is multi-layered, generally there is no method available for end users to instantly confirm the traceability from the reference standard to a primary standard. This study focuses on the Ethereum blockchain, which has both tamper resistance and high availability, as a digital data management method. To improve the transparency and reliability of calibration tests, a smart contract that traces back to the primary standard is proposed. Consequently, it is confirmed that end users can instantly obtain traceability information. In addition, the execution of smart contracts requires transaction fees. Here, the calculation of the transaction fees is organized, and the traceability management system is discussed from a cost-effective perspective in the field of metrology.
RESUMEN
Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment.
Asunto(s)
Cumarinas/química , Cumarinas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinasas raf/antagonistas & inhibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Cumarinas/farmacocinética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Haplorrinos , Ratones , Ratas , Relación Estructura-Actividad , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacocinética , Ácidos Sulfónicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/metabolismoRESUMEN
Coastal dikes are an essential social infrastructure to mitigate tsunami damage. However, there are no clear guidelines on effective dike shapes for reducing tsunami overflow. To examine effective dike shapes, numerical simulations of the amount of tsunami overflow at coastal dikes are conducted with reference to tsunami waveforms caused by the Great East Japan Earthquake. Results reveal the relationship between the dike shape and the amount of the overflow; the mechanism of overflow reduction based on the velocity and water level distribution is also verified. The comparison of the seaward and landward slopes of coastal dikes reveals that the seaward slope has a greater impact on the overflow, and the seaward slope with a vertical wall or a wave return structure reduces the overflow by 5%-30% compared to the 1:2 (26.6°) seaward slope. The landward slope should be determined based on the tsunami scale and the scour related to the dike stability. Since tsunami inflow damages human life and social infrastructure, achieving the overflow reduction without increasing dike height is vital. Our work contributes to rational design guidelines for coastal dikes.
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Terremotos , Tsunamis , Humanos , JapónRESUMEN
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Haplorrinos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivatives as potent ALK inhibitors. Among them, compound 27 showed strong cytotoxicity against KARPAS-299 with an IC(50) value of 21 nM and significant antitumor efficacy in ALK fusion-positive blood and solid cancer xenograft models in mice without body weight loss.
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Antineoplásicos/síntesis química , Descubrimiento de Drogas , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Tetraciclinas/síntesis química , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Tetraciclinas/química , Tetraciclinas/farmacologíaRESUMEN
In flow velocity measurements, resolution, miniaturization, and accuracy of measuring devices are important issues because the measuring devices significantly affect the flow in the micro-space, sonic flow, and turbulent flow. We studied recovery temperature anemometry (RTA) using micrometer-order thermometers and evaluated its validity in two velocity ranges (40-90 and 315-420 m/s) by conducting two experiments and a numerical simulation. The results confirmed that the difference between the reference velocity and RTA was within 5% in the velocity range 60-90 m/s for both the thermocouple and platinum thermometer given the same recovery temperature coefficient of 0.83. It is a valuable finding that velocity measurement by RTA is independent of the type of thermometer used. This suggests that the accuracy of about 5% can be guaranteed even without calibration by giving the recovery temperature coefficient according to the thermometer geometry, which is an excellent advantage not found in other anemometers. Furthermore, the supersonic flow measured using RTA agrees well with the simulation results and theoretical trends. Our findings ensure that the micrometer-order point measurement of flow velocity, which is difficult with existing anemometers, using RTA is possible over a wide range of flow velocities.
RESUMEN
Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.
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A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.
RESUMEN
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Piperazinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carbazoles/farmacocinética , Carbazoles/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Ratones , Ratones SCID , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacología , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
A convergent synthesis of (-)-2-epi-peloruside A has been achieved. Highlights include implementation of multicomponent type I anion relay chemistry (ARC) to unite 2-TBS-1,3-dithiane with two epoxides to construct the eastern hemisphere, a late-stage dithiane union to secure the complete, fully functionalized carbon backbone, and Yamaguchi macrolactonization, which led to (-)-2-epi-peloruside A via an unexpected epimerization at C(2).
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Aldehídos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Lactonas/síntesis química , Quinolizinas/síntesis química , Compuestos de Azufre/síntesis química , Aldehídos/química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Epoxi/química , Lactonas/química , Poríferos/química , Quinolizinas/química , Compuestos de Azufre/químicaRESUMEN
The stereocontrolled total synthesis of a C31-allenic apo-carotenoid, paracentrone, was achieved by the convergent C20 + C11 = C31 strategy. The key elements of our synthesis were the Pd-catalyzed cross-coupling to stereoselectively construct the conjugated polyene backbone skeleton and the designed geometrical isomerization at the central double bond of the conjugated polyene chain. In addition, the terminal oxygenated cyclohexane ring having the allenic moiety was prepared by the highly diastereoselective Sharpless epoxidation under our own reaction conditions.
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Carotenoides/síntesis química , Aldehídos/química , Carotenoides/química , Yoduros/química , Estructura MolecularRESUMEN
Peridinin, which was isolated from the planktonic algae dinoflagellates causing red tides, is a highly oxidized carotenoid containing an allene and a characteristic (Z)-gamma-ylidenebutenolide function in the main conjugated polyene chain in addition to functionalized cyclohexane rings at both ends of the molecule. We achieved a stereocontrolled total synthesis of peridinin by featuring the Sharpless asymmetric epoxidation under precise reaction conditions, Wittig reaction with silylfuranmethylide followed by photosensitized oxygenation, stereocontrolled Pd-catalyzed one-pot (Z)-gamma-ylidenebutenolide synthesis, and modified Julia-Kocienski olefination. This synthesis is the first example of controlling the stereochemistry of polyfunctional allenic carotenoids.