RESUMEN
Incorporation of nitrogen is a common medicinal chemistry tactic to reduce logD values. Neighboring group participation influences logD, so the results are isomer dependent. The logD and logP differences observed between isomeric pyrimidines 1, 2 and 3 presumably result when the carbonyl or ether lone pairs are in close proximity to a heterocyclic nitrogen lone pair, recruiting water to bridge between the electron rich atoms. Various lipophilicity calculators did not discriminate between 1 (logD=2.6) and 3 (logD=1.0), but solvation energies using Poisson-Boltzmann and 3D-RISM methods rationalize the observed differences in lipophilicity among pyrimidine carboxamide isomers.
Asunto(s)
Amidas/química , Electrones , Nitrógeno/química , Pirimidinas/química , Agua/química , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Isomerismo , Modelos Moleculares , Solubilidad , TermodinámicaRESUMEN
Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3Kα/mTOR dual inhibitor, is highlighted.
Asunto(s)
Diseño de Fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Piridonas/química , Pirimidinas/química , Pirimidinonas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Sitios de Unión , Cristalografía por Rayos X , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridonas/síntesis química , Piridonas/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Pirrolidinas/química , Ratas , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intravenosas , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/inmunologíaRESUMEN
Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/química , Pteridinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Humanos , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pteridinas/administración & dosificación , Pteridinas/farmacología , Solubilidad , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The crystal structure of the title compound, C(5)H(3)BrN(2)S, shows that bromination of 1H-thieno[2,3-d]imidazole with N-bromo-succinimide in acetonitrile occurs at position 5 of the bicyclic system. The mol-ecule is almost planar, with a mean deviation of 0.015â Å from the least-squares plane through all the non-H atoms. In the crystal, N-Hâ¯N hydrogen bonds link the mol-ecules into infinite C(4) chains running along [101].
RESUMEN
Checkpoints are present in all phases of the cell cycle and are regarded as the gatekeepers maintaining the integrity of the genome. Many conventional agents used to treat cancer impart damage to the genome and activate cell cycle checkpoints. Many tumors are defective in the tumor suppressor p53 and therefore lack a functional G(1) checkpoint. In these tumors, however, the S-G(2) checkpoints remain intact and, in response to DNA damage, arrest cell cycle progression allowing time for DNA repair. Checkpoint kinase 1 (Chk1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G(2)-phase checkpoints. Inhibiting Chk1 represents a therapeutic strategy for creating a "synthetic lethal" response by overriding the last checkpoint defense of tumor cells against the lethal damage induced by DNA-directed chemotherapeutic agents. Chk1 inhibition is consistent with emerging targeted therapies aiming to exploit molecular differences between normal and cancer cells. Adding a Chk1 inhibitor to DNA-damaging cytotoxic therapy selectively targets tumors with intrinsic checkpoint defects while minimizing toxicity in checkpoint-competent normal cells. PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a K(i) of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. In xenografts, PF-00477736 enhanced the antitumor activity of gemcitabine in a dose-dependent manner. PF-00477736 combinations were well tolerated with no exacerbation of side effects commonly associated with cytotoxic agents.
Asunto(s)
Benzodiazepinonas/farmacología , Daño del ADN , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/efectos de los fármacos , Pirazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cromatografía Liquida , Desoxicitidina/análogos & derivados , Desoxicitidina/antagonistas & inhibidores , Desoxicitidina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Histonas/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Fosforilación , Ratas , Ratas Sprague-Dawley , Fase S/efectos de los fármacos , Espectrometría de Masas en Tándem , GemcitabinaRESUMEN
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.
Asunto(s)
Descubrimiento de Drogas , Dolor/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Ratas , Proteínas Tirosina Quinasas Receptoras/química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Solubilidad , Relación Estructura-Actividad , Distribución TisularRESUMEN
The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Bifenilo/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/metabolismo , Pirazoles/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Neoplasias de la Mama , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cristalografía por Rayos X , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Humanos , Indazoles/química , Masculino , Modelos Moleculares , Estructura Molecular , Neoplasias de la Próstata , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , GemcitabinaRESUMEN
A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Piridonas/química , Piridonas/farmacología , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ciclización , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Lactamas/química , Lactamas/farmacología , Ratones , Ratones SCID , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Piridonas/uso terapéuticoRESUMEN
A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.