RESUMO
Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen â¼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.
Assuntos
COVID-19 , Mycobacterium tuberculosis , Animais , Indústria Farmacêutica , Camundongos , SARS-CoV-2 , Universidades , beta-Lactamas/farmacologiaRESUMO
Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Estrogênio/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Humanos , CamundongosRESUMO
More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Descoberta de Drogas/métodos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Animais , Neoplasias da Mama/metabolismo , Cristalografia por Raios X , Cães , Resistencia a Medicamentos Antineoplásicos , Feminino , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Camundongos , Modelos Moleculares , Ratos , Receptores de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inwardly rectifying IK1 potassium currents of the heart control the resting membrane potential of ventricular cardiomyocytes during diastole and contribute to their repolarization after each action potential. Mutations in the gene encoding Kir2.1 channels, which primarily conduct ventricular IK1, are associated with inheritable forms of arrhythmias and sudden cardiac death. Therefore, potential iatrogenic inhibition of Kir2.1-mediated IK1 currents is a cardiosafety concern during new drug discovery and development. Kir2.1 channels are part of the panel of cardiac ion channels currently considered for refined early compound risk assessment within the Comprehensive in vitro Proarrhythmia Assay initiative. In this study, we have validated a cell-based assay allowing functional quantification of Kir2.1 inhibitors using whole-cell recordings of Chinese hamster ovary cells stably expressing human Kir2.1 channels. We reproduced key electrophysiological and pharmacological features known for native IK1, including current enhancement by external potassium and voltage- and concentration-dependent blockade by external barium. Furthermore, the Kir inhibitors ML133, PA-6, and chloroquine, as well as the multichannel inhibitors chloroethylclonidine, chlorpromazine, SKF-96365, and the class III antiarrhythmic agent terikalant demonstrated slowly developing inhibitory activity in the low micromolar range. The robustness of this assay authorizes medium throughput screening for cardiosafety purposes and could help to enrich the currently limited Kir2.1 pharmacology.
Assuntos
Automação , Cloroquina/farmacologia , Imidazóis/farmacologia , Pentamidina/farmacologia , Fenantrolinas/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Animais , Células CHO , Cloroquina/química , Cricetulus , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos , Humanos , Imidazóis/química , Estrutura Molecular , Pentamidina/análogos & derivados , Pentamidina/química , Fenantrolinas/química , Canais de Potássio Corretores do Fluxo de Internalização/metabolismoRESUMO
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Pirimidinonas/farmacologia , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Sob a Curva , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Classe III de Fosfatidilinositol 3-Quinases/química , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Masculino , Camundongos SCID , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Neoplasias/patologia , Ligação Proteica , Estrutura Terciária de Proteína , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Homologia de Sequência de Aminoácidos , Termodinâmica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Benzimidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/química , Aurora Quinase A/metabolismo , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/química , Aurora Quinase B/metabolismo , Aurora Quinase C/antagonistas & inibidores , Aurora Quinase C/química , Aurora Quinase C/metabolismo , Aurora Quinases/química , Aurora Quinases/metabolismo , Benzimidazóis/química , Benzimidazóis/metabolismo , Feminino , Células HCT116 , Humanos , Camundongos SCID , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinolonas/química , Quinolonas/metabolismo , Células Sf9 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration-approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinonas/farmacologia , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Antineoplásicos/síntese química , Autofagia/genética , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe III de Fosfatidilinositol 3-Quinases/química , Classe III de Fosfatidilinositol 3-Quinases/genética , Sinergismo Farmacológico , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Everolimo , Expressão Gênica , Humanos , Rim/enzimologia , Rim/patologia , Cinética , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Pirimidinonas/síntese química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Transdução de Sinais , Sirolimo/síntese química , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/genéticaRESUMO
In our continuous efforts to identify and develop novel targeted cancer treatments, a new morpholino-thiazole scaffold active against PI3Kß has been identified. This Letter reports the optimization of this compound class to develop PI3Kß isoform-selective inhibitors with suitable pharmacological properties.
Assuntos
Amidas/química , Ácidos Carboxílicos/química , Indóis/química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Amidas/síntese química , Animais , Sítios de Ligação , Células CACO-2 , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Humanos , Masculino , Simulação de Acoplamento Molecular , Permeabilidade/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Tiazóis/químicaRESUMO
Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kß in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kß-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kß inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110ß with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.
Assuntos
Antineoplásicos/química , Indóis/química , Neoplasias/tratamento farmacológico , PTEN Fosfo-Hidrolase/deficiência , Inibidores de Fosfoinositídeo-3 Quinase , Pirimidinonas/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Xenoenxertos , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Microssomos Hepáticos/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Neoplasias/enzimologia , PTEN Fosfo-Hidrolase/genética , Ligação Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Ratos , Ratos Nus , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kß isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kß. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias da Próstata/tratamento farmacológico , Pirimidinonas/química , Pirimidinonas/farmacologia , Anilidas/química , Anilidas/farmacocinética , Anilidas/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Cristalografia por Raios X , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos SCID , Modelos Moleculares , PTEN Fosfo-Hidrolase/genética , Próstata/citologia , Próstata/efeitos dos fármacos , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Pirimidinonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kß has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kß-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kß and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kß isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.