RESUMO
TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no small-molecule inhibitors have been published for this challenging interface. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported. The design features the introduction of a four-carbon-atom linker into the peptide epitope found in many TLE1 binding partners. A concise synthetic route to a proof-of-concept peptide, cycFWRPW, has been developed. Biophysical testing by isothermal titration calorimetry and thermal shift assays showed that, although the constrained peptide bound potently, it had an approximately five-fold higher Kd than that of the unconstrained peptide. The co-crystal structure suggested that the reduced affinity was likely to be due to a small shift of one side chain, relative to the otherwise well-conserved conformation of the acyclic peptide. This work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors.
Assuntos
Oligopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Proteínas Repressoras/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Proteínas Correpressoras , Humanos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Oligopeptídeos/química , Peptídeos Cíclicos/química , Ligação Proteica , Conformação Proteica , Proteínas Repressoras/química , TermodinâmicaRESUMO
The total syntheses of 12-epoxyobtusallene IV, 12-epoxyobtusallene II, obtusallene X, marilzabicycloallene C, and marilzabicycloallene D as halogenated C15-acetogenin 12-membered bicyclic and tricyclic ether bromoallene-containing marine metabolites from Laurencia species are described. Two enantiomerically pure C4-epimeric dioxabicyclo[8.2.1]tridecenes were synthesized by E-selective ring-closing metathesis where their absolute stereochemistry was previously set via catalytic asymmetric homoallylic epoxidation and elaborated via regioselective epoxide-ring opening and diastereoselective bromoetherification. Epimeric face-selective oxidation of their Δ12,13 olefins followed by bromoallene installation allowed access to the oppositely configured 12,13-epoxides of 12-epoxyobtusallene II and 12-epoxyobtusallene IV. Subsequent exploration of their putative biomimetic oxonium ion formation-fragmentations reactions revealed diastereodivergent pathways giving marilzabicycloallene C and obtusallene X, respectively. The original configurations of the substrates evidently control oxonium ion formation and their subsequent preferred mode of fragmentation by nucleophilic attack at C9 or C12. Quantum modeling of this stereoselectivity at the ωB97X-D/Def2-TZVPPD/SCRF = methanol level revealed that in addition to direction resulting from hydrogen bonding, the dipole moment of the ion-pair transition state is an important factor. Marilzabicycloallene D as a pentahalogenated 12-membered bicyclic ether bromoallene was synthesized by a face-selective chloronium ion initiated oxonium ion formation-fragmentation process followed by subsequent bromoallene installation.
RESUMO
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Descoberta de Drogas , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/químicaRESUMO
We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R)-21, a potent and selective inhibitor able to modulate Nek2 activity in cells.
Assuntos
Aminopiridinas/síntese química , Antineoplásicos/síntese química , Benzamidas/síntese química , Mitose , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Alcenos/síntese química , Alcenos/química , Alcenos/farmacologia , Aminopiridinas/química , Aminopiridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Estrutura Molecular , Quinases Relacionadas a NIMA , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologiaRESUMO
We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.
Assuntos
Benzamidas/síntese química , Benzimidazóis/síntese química , Modelos Moleculares , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Feminino , Humanos , Técnicas In Vitro , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Quinases Relacionadas a NIMA , Fosforilação , Ligação Proteica , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.
Assuntos
Modelos Moleculares , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/síntese química , Cristalografia por Raios X , Humanos , Quinases Relacionadas a NIMA , Fosforilação , Ligação Proteica , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Pirazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.
Assuntos
Bromo/química , Éteres Cíclicos/química , Oxigênio/química , Ciclização , Éteres Cíclicos/síntese química , Íons/química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
[reaction: see text] Sharpless asymmetric dihydroxylation was regioselective for the trans olefin in an E vs Z vs terminal triene substrate. To test a biosynthetic hypothesis, the resulting diol underwent diastereoselective bromoetherification to provide the des-chloro core of marine natural products obtusallenes II and IV. Alternatively, anionic chloride ring-opening of a Z-beta,gamma-unsaturated epoxide gave separable regioisomeric halohydrins. Bromoetherification gave the fully elaborated core of obtusallenes II and IV with all of the relative stereochemistry correctly set.