RESUMO
Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.
Assuntos
Transtornos Relacionados ao Uso de Opioides , Dor , Ratos , Animais , Dor/tratamento farmacológico , Amidas , Encéfalo/metabolismo , Receptores Opioides mu/agonistas , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêuticoRESUMO
2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Masculino , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
Assuntos
Acetatos/farmacologia , Descoberta de Drogas , Piperidonas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sulfonamidas/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Piperidonas/química , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/química , Ratos , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/químicaRESUMO
The discovery, structure-based design, synthesis, and optimization of NIK inhibitors are described. Our work began with an HTS hit, imidazopyridinyl pyrimidinamine 1. We utilized homology modeling and conformational analysis to optimize the indole scaffold leading to the discovery of novel and potent conformationally constrained inhibitors such as compounds 25 and 28. Compounds 25 and 31 were co-crystallized with NIK kinase domain to provide structural insights.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Alcinos/síntese química , Alcinos/química , Alcinos/farmacologia , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Desenho de Fármacos , Células HT29 , Humanos , Ligação de Hidrogênio , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/química , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Quinase Induzida por NF-kappaBRESUMO
PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
Assuntos
PPAR gama/agonistas , Quinolinas/química , Sulfonamidas/química , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Meia-Vida , Resistência à Insulina , Masculino , Camundongos , PPAR gama/metabolismo , Estrutura Terciária de Proteína , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.
Assuntos
Acetatos/síntese química , Antineoplásicos/síntese química , Piperidonas/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Amino Álcoois/síntese química , Amino Álcoois/química , Antineoplásicos/química , Ciclização , Humanos , Lactonas/síntese química , Lactonas/química , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/química , Piperidonas/química , EstereoisomerismoRESUMO
A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model.
Assuntos
Anti-Inflamatórios/química , Benzenoacetamidas/química , Óxidos S-Cíclicos/química , Imidazóis/química , Pirazinas/química , Receptores CXCR3/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Benzenoacetamidas/síntese química , Benzenoacetamidas/farmacocinética , Óxidos S-Cíclicos/síntese química , Óxidos S-Cíclicos/farmacocinética , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Camundongos , Conformação Molecular , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Receptores CXCR3/metabolismoRESUMO
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.
Assuntos
Compostos Heterocíclicos/farmacologia , Quinazolinonas/farmacologia , Receptores CXCR3/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Quinazolinonas/farmacocinética , Ratos , EstereoisomerismoRESUMO
The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.
Assuntos
Descoberta de Drogas , Antagonistas de Hormônios/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Feminino , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacocinética , Humanos , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ratos , Suínos , Porco Miniatura , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Cristalografia por Raios X , Hemocianinas/efeitos dos fármacos , Humanos , Imunoglobulina G/efeitos dos fármacos , Imunoglobulina M/efeitos dos fármacos , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
Assuntos
Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Resistance to FLT3 inhibitors is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG 925, a dual FLT3/CDK4 inhibitor, has been developed to overcome this resistance. It is hypothesized that the combined inhibition of FLT3 and CDK4 may reduce occurrence of the FLT3 resistance mutations, and thereby prolong clinical responses. To test this hypothesis, we attempted to isolate AML cell clones resistant to AMG 925 or to FLT3 inhibitors. After a selection of over 8 months with AMG 925, we could only isolate partially resistant clones. No new mutations in FLT3 were found, but a 2- to 3-fold increase in total FLT3 protein was detected and believed to contribute to the partial resistance. In contrast, selection with the FLT3 inhibitors sorafenib or AC220 (Quizartinib), led to a resistance and the appearance of a number of mutations in FLT3 kinase domains, including the known hot spot sites D835 and F691. However, when AC220 was combined with the CDK4 inhibitor PD0332991 (palbociclib) at 0.1 µmol/L or higher, no resistance mutations were obtained, indicating that the CDK4-inhibiting activity of AMG 925 contributed to the failure to develop drug resistance. AMG 925 was shown to potently inhibit the FLT3 inhibitor-resistant mutation D835Y/V. This feature of AMG 925 was also considered to contribute to the lack of resistance mutations to the compound. Together, our data suggest that AMG 925 has the potential to reduce resistance mutations in FLT3 and may prolong clinical responses.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Leucemia Mieloide Aguda/patologia , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Separação Celular , Células Clonais , Quinase 4 Dependente de Ciclina/metabolismo , Humanos , Mutação/genética , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Assuntos
Adenosina/farmacologia , Doenças Autoimunes/prevenção & controle , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inflamação/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Adenosina/química , Adenosina/metabolismo , Animais , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinolinas/química , Quinolinas/metabolismo , Ratos Endogâmicos Lew , Células Sf9 , Relação Estrutura-AtividadeRESUMO
NFkB activity is critical for survival and proliferation of normal lymphoid cells and many kinds of B-cell tumors, including multiple myeloma (MM). NFkB activating mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NFkB. Mutations that activate NFkB-inducing kinase (NIK) protein are the most prevalent among the many kinds of NFkB mutations in MM tumors. NIK is the main activating kinase of the alternative NFkB pathway, although over-expression of NIK also can activate the classical pathway. Two NIK inhibitors and an isomeric control were tested with human myeloma cell lines. These specific NIK inhibitors are selectively cytotoxic for cells with NIK-dependent activation of NFkB. Combination therapy targeting NIK and IKKbeta (as a main kinase of the classical NFkB pathway) represents a promising treatment strategy in MM. NIK inhibitors can also be useful tool for assessing the role of NIK and alternative NFkB pathway in different cells.
Assuntos
Linfócitos B/metabolismo , Mieloma Múltiplo/metabolismo , NF-kappa B/metabolismo , Citotoxicidade Imunológica , Humanos , Transdução de SinaisRESUMO
Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Naftiridinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Neoplasias Experimentais , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Células U937 , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Descoberta de Drogas , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/química , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismoRESUMO
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Morfolinas/síntese química , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/química , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Indicadores e Reagentes , Camundongos , Modelos Moleculares , Conformação Molecular , Morfolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Piperidonas/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Animais , Neoplasias Ósseas/tratamento farmacológico , Ácidos Carboxílicos/química , Células Cultivadas , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Humanos , Ligação de Hidrogênio , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Osteossarcoma/tratamento farmacológico , Piperidonas/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Piperidonas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Administração Oral , Antineoplásicos/química , Disponibilidade Biológica , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Piperidonas/química , Conformação ProteicaRESUMO
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.