RESUMO
PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R 2 = 0.7, Q 2 = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs.
Assuntos
Modelos Biológicos , Pesquisa Farmacêutica/métodos , Polímeros/farmacologia , Relação Quantitativa Estrutura-Atividade , Administração Oral , Simulação por Computador , Interações Medicamentosas , Trânsito Gastrointestinal , Interações Hidrofóbicas e Hidrofílicas , Modelos Lineares , Estrutura Molecular , Polímeros/químicaRESUMO
The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
Assuntos
Descoberta de Drogas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Pirimidinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-AtividadeRESUMO
SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile.
RESUMO
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
Assuntos
Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Antineoplásicos/química , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chk1 is a serine/threonine kinase that plays several important roles in the cellular response to genotoxic stress. Since many current standard-of-care therapies for human cancer directly damage DNA or inhibit DNA synthesis, there is interest in using small molecule inhibitors of Chk1 to potentiate their clinical activity. Additionally, Chk1 is known to be critically involved in cell cycle progression of unperturbed cells. Therefore, it is plausible that treatment with a Chkl inhibitor alone could also be an efficacious cancer therapy. Here we report that Chk1-A, a potent and highly selective small molecule inhibitor of Chk1, is antiproliferative as a single agent in a variety of human cancer cell lines in vitro. The inhibition of proliferation is associated with collapse of DNA replication and apoptosis. Rapid decreases in inhibitory phosphorylation of CDKs and a concomitant increase in CDK kinase activity and chromatin loading of Cdc45 suggest that the antiproliferative and proapoptotic activity of Chk1-A is at least in part due to deregulation of DNA synthesis. We extend these in vitro studies by demonstrating that Chk1-A inhibits the growth of tumor xenografts in vivo in a treatment regimen that is well tolerated. Together, these results suggest that single-agent inhibition of Chk1 may be an effective treatment strategy for selected human malignancies.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/fisiologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-AtividadeRESUMO
We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Compostos de Espiro/química , Sulfonamidas/química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/química , Pirróis/química , Proteínas Adaptadoras de Transdução de Sinal , Animais , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Fosfoproteínas/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/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.
Assuntos
Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/química , Animais , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Carga Tumoral/efeitos dos fármacosRESUMO
INTRODUCTION: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. METHODS: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays. RESULTS: After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs. CONCLUSIONS: RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.
Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-ret , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis , Piridinas , Solventes , TransfecçãoRESUMO
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure-activity relationships are detailed, along with enzyme and cellular activity.
Assuntos
Inibidores Enzimáticos/farmacologia , Isoquinolinas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Inibidores Enzimáticos/química , Isoquinolinas/química , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hepacivirus/efeitos dos fármacos , Tiazinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Biologia Computacional , Simulação por Computador , Cristalografia por Raios X , RNA Polimerases Dirigidas por DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ligação Proteica , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Tiazóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Haplorrinos , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Proteínas não Estruturais Virais/metabolismoRESUMO
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirrolidinonas/química , Tiazinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
Assuntos
Antivirais/química , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/química , Hepacivirus/efeitos dos fármacos , Quinolinas/química , Quinolonas/química , Tiazinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Simulação por Computador , Cristalografia por Raios X , RNA Polimerases Dirigidas por DNA/metabolismo , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolonas/síntese química , Quinolonas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.
RESUMO
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Células NIH 3T3 , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/genética , Receptor trkA/metabolismoRESUMO
The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Piridinas/síntese química , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Fosforilação , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.