RESUMEN
Evidence shows that charge carriers in organic semiconductors self-localize because of dynamic disorder. Nevertheless, some organic semiconductors feature reduced mobility at increasing temperature, a hallmark for delocalized band transport. Here we present the temperature-dependent mobility in two record-mobility organic semiconductors: dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]-thiophene (DNTT) and its alkylated derivative, C8-DNTT-C8. By combining terahertz photoconductivity measurements with atomistic non-adiabatic molecular dynamics simulations, we show that while both crystals display a power-law decrease of the mobility (µ) with temperature (T) following µ â T -n, the exponent n differs substantially. Modelling reveals that the differences between the two chemically similar semiconductors can be traced to the delocalization of the different states that are thermally accessible by charge carriers, which in turn depends on their specific electronic band structure. The emerging picture is that of holes surfing on a dynamic manifold of vibrationally dressed extended states with a temperature-dependent mobility that provides a sensitive fingerprint for the underlying density of states.
RESUMEN
Fast and accurate estimation of electronic coupling matrix elements between molecules is essential for the simulation of charge transfer phenomena in chemistry, materials science, and biology. Here we investigate neural-network-based coupling estimators combined with different protocols for sampling reference data (random, farthest point, and query by committee) and compare their performance to the physics-based analytic overlap method (AOM), introduced previously. We find that neural network approaches can give smaller errors than AOM, in particular smaller maximum errors, while they require an order of magnitude more reference data than AOM, typically one hundred to several hundred training points, down from several thousand required in previous ML works. A Δ-ML approach taking AOM as a baseline is found to give the best overall performance at a relatively small computational overhead of about a factor of 2. Highly flexible π-conjugated organic molecules like non-fullerene acceptors are found to be a particularly challenging case for ML because of the varying (de)localization of the frontier orbitals for different intramolecular geometries sampled along molecular dynamics trajectories. Here the local symmetry functions used in ML are insufficient, and long-range descriptors are expected to give improved performance.
RESUMEN
As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).
Asunto(s)
Ciclohexilaminas/farmacología , Descubrimiento de Drogas , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Ciclohexilaminas/uso terapéutico , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fosforilación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Antineoplásicos , Neoplasias de la Mama , Línea Celular Tumoral , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A robust understanding of the mechanoelectric response of organic semiconductors is crucial for the development of materials for flexible electronics. In particular, the prospect of using external mechanical strain to induce a controlled modulation in the charge mobility of the material is appealing. Here we develop an accurate computational protocol for the prediction of the mechanical strain dependence of charge mobility. Ab initio molecular dynamics simulations with a van der Waals density functional are carried out to quantify the off-diagonal electronic disorder in the system as a function of strain by the explicit calculation of the thermal distributions of electronic coupling matrix elements. The approach is applied to a representative molecular organic semiconductor, single-crystal rubrene. We find that charge mobility along the high-mobility direction aâ increases with compressive strain, as one might expect. However, the increase is larger when compressive strain is applied in the perpendicular direction than in the parallel direction with respect to aâ, in agreement with experimental reports. We show that this seemingly counterintuitive result is a consequence of a significantly greater suppression of electronic coupling fluctuations in the range of 50-150 cm-1, when strain is applied in the perpendicular direction. Thus our study highlights the importance of considering off-diagonal electron-phonon coupling in understanding the mechanoelectric response of organic semiconducting crystals. The computational approach developed here is well suited for the accurate prediction of strain-charge mobility relations and should provide a useful tool for the emerging field of molecular strain engineering.
RESUMEN
Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Docetaxel/uso terapéutico , Diseño de Fármacos , Femenino , Ratones SCID , Proteínas Asociadas a Microtúbulos/metabolismo , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Ratones , Mitosis/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Empalme del ARN/efectos de los fármacos , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/enzimologíaRESUMEN
We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/química , Pirazinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triazoles/química , Triazoles/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazinas/metabolismo , Pirazinas/farmacocinética , Ratas , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismo , Triazoles/metabolismo , Triazoles/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Pirazinas/síntesis química , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Heterocyclic dopamine surrogates of types 5 and 7 were synthesized and investigated for their dopaminergic properties. The enantiomerically pure biphenylcarboxamide (S)-5a displayed an outstanding K(i) of 27 pM at the agonist-labeled D(3) receptor and significant selectivity over the D(2) subtype. Measurement of [(35)S]GTPγS incorporation in the presence of a coexpressed PTX-insensitive G(α0-1) subunit indicated highly efficient G-protein coupling. Comparison of ligand efficacy data from cAMP accumulation and [(3)H]thymidine incorporation experiments revealed that ligand biased signaling is exerted by the test compound (S)-5a. Starting from the D(3) crystal structure, a combination of homology modeling and site directed mutagenesis gave valuable insights into the binding mode and the intermolecular origins of stereospecific receptor recognition. According to these data, the superior affinity of the eutomer 5a is caused by the favorable binding energy that results from interaction between the ligand's central ammonium unit and the aspartate residue in position 3.32 of the receptor.
Asunto(s)
Pirazoles/química , Pirazoles/metabolismo , Piridinas/química , Piridinas/metabolismo , Receptores de Dopamina D3/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Unión Proteica , Conformación Proteica , Pirazoles/síntesis química , Piridinas/síntesis química , Receptores de Dopamina D3/química , Receptores de Dopamina D3/genética , Estereoisomerismo , Especificidad por SustratoRESUMEN
Employing 1,3-dipolar cycloaddition for the synthesis of the 7a-azaindole nucleus, analogues of melatonin have been synthesized and tested against human and amphibian melatonin receptors. Introducing a phenyl substituent in position 2 of the heterocyclic moiety significantly increased binding affinity to both the MT1 and MT2 receptors. Shifting the methoxy group from position 5 to 2 of the 7a-azaindole ring led to a substantial reduction of MT1 binding when MT2 recognition was maintained. We theoretically investigated the hypothesis whether the 2-methoxy function of the azamelatonin analogue 27 is able to mimic the 5-methoxy group of the neurohormone by directing its 2-methoxy function toward the methoxy binding site. DFT calculations and experimental binding differences of analogue compounds indicate that the energy gained by forming the methoxy-specific hydrogen-bond interaction should exceed the energy required for adopting an alternative conformation.
Asunto(s)
Melatonina/análogos & derivados , Nitrógeno/química , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/química , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/química , Animales , Unión Competitiva/efectos de los fármacos , Línea Celular , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Melatonina/química , Melatonina/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Células 3T3 NIH , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genética , Relación Estructura-Actividad , XenopusRESUMEN
Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.