RESUMO
We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Hidantoínas/química , Inibidores de Proteases/química , Proteína ADAM17/metabolismo , Animais , Área Sob a Curva , Cães , Ativação Enzimática/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Hidantoínas/síntese química , Hidantoínas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Curva ROC , Ratos , Relação Estrutura-AtividadeRESUMO
Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.
Assuntos
Antineoplásicos/síntese química , Neoplasias Encefálicas/tratamento farmacológico , Cinesinas/antagonistas & inibidores , Compostos de Espiro/síntese química , Tiadiazóis/síntese química , Moduladores de Tubulina/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Células HCT116 , Histonas/metabolismo , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Masculino , Camundongos , Permeabilidade , Piperidinas/química , Pirimidinas/química , Pirróis/química , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia , Tionas/química , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005µM.
Assuntos
Ciclina A/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Cristalografia por Raios X , Ciclina A/química , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/química , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Pirrolidinas/química , Tartaratos/química , Proteína ADAM17 , Amidas/síntese química , Amidas/química , Animais , Disponibilidade Biológica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , RatosRESUMO
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/química , Animais , Aurora Quinase A , Aurora Quinases , Avaliação Pré-Clínica de Medicamentos , Imidazóis/síntese química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , RatosRESUMO
A novel series of CHK1 inhibitors based on thienopyridine template has been designed and synthesized. These inhibitors maintain critical hydrogen bonding with the hinge and conserved water in the ATP binding site. Several compounds show single digit nanomolar CHK1 activities. Compound 70 shows excellent enzymatic activity of 1 nM.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/química , Piridazinas/síntese química , Tienopiridinas/química , Tiofenos/síntese química , Trifosfato de Adenosina/química , Sítios de Ligação , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Piridazinas/química , Piridazinas/farmacologia , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/farmacologia , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/química , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteases/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Cães , Haplorrinos , Humanos , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , RatosRESUMO
Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzopiranos/administração & dosagem , Benzopiranos/farmacologia , Cinesinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Tiadiazóis/administração & dosagem , Tiadiazóis/farmacologia , Administração Oral , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Células HCT116 , Haplorrinos , Humanos , Camundongos , Camundongos Nus , Neoplasias/patologia , Ratos , Resultado do Tratamento , Células Tumorais CultivadasRESUMO
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Administração Oral , Animais , Aurora Quinases , Disponibilidade Biológica , Linhagem Celular Tumoral , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/química , Pirazinas/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteína ADAM17 , Animais , Ratos , Relação Estrutura-AtividadeRESUMO
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/química , Tartaratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Sítios de Ligação , Simulação por Computador , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tartaratos/síntese química , Tartaratos/farmacocinéticaRESUMO
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hidantoínas/farmacologia , Proteína ADAM17 , Inibidores Enzimáticos/química , Hidantoínas/química , Ligação de Hidrogênio , Modelos Moleculares , Relação Estrutura-Atividade , Difração de Raios XRESUMO
The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 µM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.
RESUMO
This manuscript describes an affinity selection-mass spectrometry (AS-MS) method for quantitative protein-ligand binding affinity (Kd) measurements in large compound libraries. The ability of a titrant ligand to displace a target-bound library member-as measured by MS-reveals the affinity ranking of the mixture component relative to "internal affinity calibrants", compounds of known affinity for the target. This technique does not require that the precise concentration of each ligand is known; therefore, unpurified products of mixture-based combinatorial synthesis may be used for affinity optimization and developing structure-activity relationships. The method is demonstrated for a series of ligands to the important oncology target CDK2 that were discovered by AS-MS screening of combinatorial libraries against the basal form of the protein. AS-MS displacement curves for select hits were acquired over a range of compound concentrations, confirming that binding affinity measurement results are concentration-insensitive. These hits were evaluated in pools of purified compounds to verify the method's applicability to hit triage in large chemical libraries. The method was further tested using unpurified, mixture-based combinatorial libraries of >1000 compounds, yielding results that mirror those obtained from mixtures of purified compounds. The technique was then used to identify optimized CDK2 ligands from compound mixtures, quantitatively measure their affinities, and establish structure-activity relationships among these drug leads.