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1.
Anal Chem ; 91(21): 13874-13882, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31584812

RESUMO

This work represents the first reporting of a comprehensive bioanalytical GLP methodology detailing the mass spectrometric quantitation of PF-05212384 dosed as a targeted polymeric encapsulated nanoparticle (PF-07034663) to monkeys. Polymeric nanoparticles are a type of drug formulation that enables the sustained release of an active therapeutic agent (payload) for targeted delivery to specific sites of action such as cancer cells. Through the careful design and engineering of the nanoparticle formulation, it is possible to improve the biodistribution and safety of a given therapeutic payload in circulation. However, the bioanalysis of nanoparticles is challenging due to the complexity of the nanoparticle drug formulation itself and the number of pharmacokinetic end points needed to characterize the in vivo exposure of the nanoparticles. Gedatolisib, also known as PF-05212384, was reformulated as an encapsulated targeted polymeric nanoparticle. The bioanalytical assays were validated to quantitate both total and released PF-05212384 derived from the encapsulated nanoparticle (PF-07034663). Assay performance calculated from quality control samples in three batch runs demonstrated intraday precision and accuracy within 10.3 and 12.2%, respectively, and interday precision and accuracy within 9.1 and 8.5%, respectively. This method leveraged automation to ease the burden of a laborious and complicated sample pretreatment and extraction procedure. The automated method was used to support a preclinical safety study in monkeys in which both released and total PF-05212384 concentrations were determined in over 1600 monkey plasma study samples via LC-MS/MS.


Assuntos
Morfolinas/administração & dosagem , Nanopartículas/análise , Polímeros/química , Triazinas/administração & dosagem , Animais , Cromatografia Líquida/métodos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Humanos , Morfolinas/farmacocinética , Nanopartículas/química , Nanopartículas/uso terapêutico , Polímeros/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual , Triazinas/farmacocinética
2.
Xenobiotica ; 47(7): 600-606, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27435693

RESUMO

1. Leukotriene B4 (LTB4) is a proinflammatory mediator important in the progression of a number of inflammatory diseases. Preclinical models can explore the role of LTB4 in pathophysiology using tool compounds, such as CP-105696, that modulate its activity. To support preclinical pharmacology studies, micro-sampling techniques and mathematical modeling were used to determine the pharmacokinetics of CP-105696 in mice within the context of systemic inflammation induced by a high-fat diet (HFD). 2. Following oral administration of doses > 35 mg/kg, CP-105696 kinetics can be described by a one-compartment model with first order absorption. The compound's half-life is 44-62 h with an apparent volume of distribution of 0.51-0.72 L/kg. Exposures in animals fed an HFD are within 2-fold of those fed a normal chow diet. Daily dosing at 100 mg/kg was not tolerated and resulted in a >20% weight loss in the mice. 3. CP-105696's long half-life has the potential to support a twice weekly dosing schedule. Given that most chronic inflammatory diseases will require long-term therapies, these results are useful in determining the optimal dosing schedules for preclinical studies using CP-105696.


Assuntos
Benzopiranos/farmacocinética , Ácidos Carboxílicos/farmacocinética , Leucotrieno B4/antagonistas & inibidores , Administração Oral , Animais , Dieta Hiperlipídica , Meia-Vida , Inflamação , Camundongos , Modelos Biológicos , Neutrófilos
3.
J Med Chem ; 64(13): 9056-9077, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34110834

RESUMO

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.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Injeções Intravenosas , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Cancer Cell ; 39(10): 1404-1421.e11, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34520734

RESUMO

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.


Assuntos
Ciclo Celular/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Feminino , Humanos , Masculino , Neoplasias/imunologia
5.
J Med Chem ; 64(1): 644-661, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356246

RESUMO

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.


Assuntos
Desenho de Fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Ratos , Espectrometria de Massas por Ionização por Electrospray/métodos
6.
Eur J Pharm Sci ; 155: 105541, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32927071

RESUMO

Human liver microsomes (HLM) and human hepatocytes (HHEP) are two common in vitro systems used in metabolic stability and inhibition studies. The comparison between the assays using the two systems can provide mechanistic insights on the interplay of metabolism, passive permeability and transporters. This study investigated the critical factors impacting the unbound intrinsic clearance (CLint,u) and IC50 of CYP3A inhibition between HLM and HHEP. The HLM/HHEP CLint,u ratio and HHEP/HLM IC50 ratio are inversely correlated to passive permeability, but have no correlation with P-gp efflux ratio. Cofactor-supplemented permeabilized HHEP (MetMax™) collapses the IC50 differences between HHEP and HLM. P-gp inhibitor, encequidar, shows minimal impact on CLint,u and IC50 in HHEP. This is the first study that is able to separately investigate the effects of passive permeability and efflux transport. These data collectively show that passive permeability plays a critical role in metabolism and enzyme inhibition in HHEP, while P-gp efflux has a minor role. This may be due to low functional P-gp activity in suspension HHEP under the assay conditions. Low passive permeability may limit metabolism and enzyme inhibition in HHEP, leading to lower CLint,u and higher IC50 in HHEP compared to HLM. When liver microsomes give higher CLint,u than hepatocytes, microsomes are more predictive of in vivo clearance than hepatocytes.


Assuntos
Hepatócitos , Microssomos Hepáticos , Transporte Biológico , Humanos , Cinética , Fígado/metabolismo , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo
7.
Clin Pharmacol Drug Dev ; 8(1): 22-31, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256541

RESUMO

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion. The only observed drug-related material in plasma was the parent drug, gedatolisib. Terminal half-life for plasma gedatolisib was ∼37 hours. Following the dose, 66%-73% of drug-related material was recovered in the feces. Metabolism of gedatolisib was trace; only 1 oxidative metabolite, M5, was identified in feces (<1% of total dose). Identification of gedatolisib in feces suggests that biliary and/or intestinal secretion of unchanged parent drug significantly contributes to gedatolisib clearance.


Assuntos
Morfolinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Triazinas/farmacocinética , Adulto , Células Cultivadas , Jejum/metabolismo , Fezes/química , Voluntários Saudáveis , Hepatócitos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/sangue , Morfolinas/urina , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Triazinas/administração & dosagem , Triazinas/sangue , Triazinas/urina
8.
Clin Cancer Res ; 23(4): 1080-1090, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27551002

RESUMO

Purpose: The translation of nonclinical oncology studies is a subject of continuous debate. We propose that translational oncology studies need to optimize both pharmacokinetic (drug exposure) and pharmacodynamic (xenograft model) aspects. While improvements in pharmacodynamic translatability can be obtained by choosing cell lines or patient-derived xenograft models closer to the clinical indication, significant ambiguity and variability exists when optimizing the pharmacokinetic translation of small molecule and biotherapeutic agents.Experimental Design and Results: In this work, we propose a pharmacokinetic-based strategy to select nonclinical doses for approved drug molecules. We define a clinically relevant dose (CRD) as the dosing regimen in mice that most closely approximates the relevant pharmacokinetic metric in humans. Such metrics include area under the time-concentration curve and maximal or minimal concentrations within the dosing interval. The methodology is applied to six drugs, including targeted agents and chemotherapeutics, small and large molecules (erlotinib, dasatinib, vismodegib, trastuzumab, irinotecan, and capecitabine). The resulting efficacy response at the CRD is compared with clinical responses.Conclusions: We conclude that nonclinical studies designed with the appropriate CRDs of approved drug molecules will maximize the translatability of efficacy results, which is critical when testing approved and investigational agents in combination. Clin Cancer Res; 23(4); 1080-90. ©2016 AACR.


Assuntos
Relação Dose-Resposta a Droga , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacocinética , Animais , Humanos , Oncologia/tendências , Camundongos , Neoplasias/patologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Pesquisa Translacional Biomédica/tendências , Ensaios Antitumorais Modelo de Xenoenxerto
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