RESUMO
Overexpression of PIM 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetra-substituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.
Assuntos
Cicloexanóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Linhagem Celular Tumoral , Cicloexanóis/síntese química , Cicloexanóis/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Relação Estrutura-AtividadeRESUMO
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Assuntos
Antineoplásicos/química , Descoberta de Drogas/métodos , Mutação/genética , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Antineoplásicos/farmacologia , Desenho de Fármacos , Descoberta de Drogas/tendências , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Acoplamento Molecular/tendências , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Fluoroquinolonas/síntese química , Fluoroquinolonas/metabolismo , Fluoroquinolonas/toxicidade , Bactérias Gram-Negativas/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/toxicidadeRESUMO
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.
Assuntos
Amidoidrolases/antagonistas & inibidores , Isoxazóis/química , Isoxazóis/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação MolecularRESUMO
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor-derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537-48. ©2018 AACR.
Assuntos
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Quinases raf/antagonistas & inibidores , Proteínas ras/genética , 2,2'-Dipiridil/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Camundongos Nus , Mutação , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/metabolismoRESUMO
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
Assuntos
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Quinases raf/antagonistas & inibidores , Proteínas ras/genética , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Cristalografia por Raios X , Cães , Desenho de Fármacos , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Camundongos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.
Assuntos
Antibacterianos/síntese química , Cetolídeos/síntese química , Compostos de Vinila/síntese química , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Disponibilidade Biológica , Farmacorresistência Bacteriana , Enterococcus faecalis/efeitos dos fármacos , Infecções por Haemophilus/tratamento farmacológico , Haemophilus influenzae/efeitos dos fármacos , Meia-Vida , Cetolídeos/farmacocinética , Cetolídeos/farmacologia , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Infecções Pneumocócicas/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Compostos de Vinila/farmacocinética , Compostos de Vinila/farmacologiaRESUMO
Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.
Assuntos
Antineoplásicos/síntese química , Piridonas/síntese química , Pirimidinas/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Camundongos , Piridonas/farmacocinética , Piridonas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis of C(12) des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C(12) stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant erm- and mef-containing strains of Streptococcus pneumoniae.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbono/química , Cetolídeos/química , Cetolídeos/farmacologia , Antibacterianos/química , Cocos Gram-Positivos/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/síntese química , Metilação , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Tiofenos/química , Tiofenos/síntese química , Linhagem Celular Tumoral , Proliferação de Células , Cristalização , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The hydrophobic component to the binding affinities of one acyclic phosphinate (4) and three macrocyclic phosphonamidate inhibitors (1-3) to the zinc peptidase thermolysin was probed by varying the solvent composition. Increasing the percentage of ethanol in the buffer solution over the range 0-9% increases the inhibition constants, K(i), by up to an order of magnitude. This approach represents an experimental method for distinguishing solvation from conformational or other effects on protein-ligand binding. The size of the "antihydrophobic effect" is correlated with the amount of hydrophobic surface area sequestered from solvent on association of the inhibitor and enzyme, although it is attenuated from that calculated from the surface tension of ethanol-water mixtures. The results are consistent with the Lum-Chandler-Weeks explanation for the size dependence of the hydrophobic effect.