RESUMO
The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.
RESUMO
This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos , Proliferação de Células , Ensaios de Triagem em Larga Escala , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Sinalização YAP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Camundongos , Proteínas rho de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Linhagem Celular Tumoral , Fosfoproteínas/metabolismo , Fosfoproteínas/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Alquil e Aril Transferases/antagonistas & inibidores , Alquil e Aril Transferases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Descoberta de Drogas , Camundongos Nus , Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Fenótipo , Relação Estrutura-Atividade , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.
Assuntos
Anticorpos Monoclonais/farmacocinética , Modelos Biológicos , Animais , Anticorpos Monoclonais/sangue , Transporte Biológico , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Camundongos , Distribuição TecidualRESUMO
During preclinical development of a gestagenic drug, a significant increase of the total plasma concentration was observed after multiple dosing in pregnant rabbits, but not in (non-pregnant) rats or monkeys. We used a PBPK modeling approach in combination with in vitro and in vivo data to address the question to what extent the pharmacologically active free drug concentration is affected by pregnancy induced processes. In human, a significant increase in sex hormone binding globulin (SHBG), and an induction of hepatic CYP3A4 as well as plasma esterases is observed during pregnancy. We find that the observed increase in total plasma trough levels in rabbits can be explained as a combined result of (i) drug accumulation due to multiple dosing, (ii) increase of the binding protein SHBG, and (iii) clearance induction. For human, we predict that free drug concentrations in plasma would not increase during pregnancy above the steady state trough level for non-pregnant women.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Especificidade de Órgãos/fisiologia , Progestinas/sangue , Progestinas/farmacocinética , Globulina de Ligação a Hormônio Sexual/análise , Algoritmos , Animais , Anticoncepcionais Orais Combinados/farmacocinética , Citocromo P-450 CYP3A/análise , Feminino , Haplorrinos , Humanos , Modelos Biológicos , Gravidez , Ligação Proteica , Coelhos , Ratos , Globulina de Ligação a Hormônio Sexual/metabolismoRESUMO
In drug discovery and development, classical compartment models and physiologically based pharmacokinetic (PBPK) models are successfully used to analyze and predict the pharmacokinetics of drugs. So far, however, both approaches are used exclusively or in parallel, with little to no cross-fertilization. An approach that directly links classical compartment and PBPK models is highly desirable. We derived a new mechanistic lumping approach for reducing the complexity of PBPK models and establishing a direct link to classical compartment models. The proposed method has several advantages over existing methods: Perfusion and permeability rate limited models can be lumped; the lumped model allows for predicting the original organ concentrations; and the volume of distribution at steady state is preserved by the lumping method. To inform classical compartmental model development, we introduced the concept of a minimal lumped model that allows for prediction of the venous plasma concentration with as few compartments as possible. The minimal lumped parameter values may serve as initial values for any subsequent parameter estimation process. Applying our lumping method to 25 diverse drugs, we identified characteristic features of lumped models for moderate-to-strong bases, weak bases and acids. We observed that for acids with high protein binding, the lumped model comprised only a single compartment. The proposed lumping approach established for the first time a direct derivation of simple compartment models from PBPK models and enables a mechanistic interpretation of classical compartment models.