Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Nature ; 588(7838): 509-514, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32927473

RESUMO

The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology1, and more recently in immunotherapy2,3 and ageing4. However, many MEK inhibitors are limited owing to on-target toxicities5-7 and drug resistance8-10. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.


Assuntos
Quinases de Proteína Quinase Ativadas por Mitógeno/química , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Piridonas/química , Piridonas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Sequência de Aminoácidos , Animais , Sítios de Ligação/efeitos dos fármacos , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Especificidade por Substrato , Quinases raf/química , Quinases raf/metabolismo
2.
J Cancer Educ ; 38(1): 134-140, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-34651280

RESUMO

Clinical rotations are often not included in graduate-level cancer biology curricula; however, basic insight into clinical oncology is often crucial for developing translational research that addresses unmet needs with the potential to benefit cancer patients. We describe a needs assessment, design, implementation, and descriptive evaluation of an oncology-specific pilot clinical encounter program developed for PhD students in the Cancer Biology Training Area (CAB) in the Graduate School of Biomedical Sciences (GSBS) and Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai (ISMMS). Prior to the development of this pilot program, CAB students, in years 2-5 + , were surveyed to determine their interest in a structured clinical experience. Seventeen out of thirty-one students responded (55%) to the survey. Of those seventeen respondents, fifteen (88.2%) expressed that exposure to cancer patients in the clinical setting would be useful for their pre-doctoral biomedical science and cancer biology training and indicated an interest in participating in the clinical encounter program. Based on these responses, a three-session clinical encounter pilot program was designed. Two separate cohorts of 5 students participated in this pilot program. During a formal debrief, following the clinical experience, students commented on the resilience of patients and the importance of research on clinical decision making, and reported that they found the experience motivational. Five out of 10 students responded (50%) to a post-program assessment survey; all five respondents answered that they would recommend the clinical encounter program to their peers. While limited in size and scope, this pilot TCI Clinical Encounter Program proved feasible and has the potential to enrich and inform the experience of PhD students pursing advanced degrees in a cancer biology.


Assuntos
Neoplasias , Estudantes , Humanos , Estudos de Viabilidade , Educação de Pós-Graduação , Biologia
3.
Biochemistry ; 60(4): 289-302, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33440120

RESUMO

Pseudokinases play important roles in signal transduction and cellular processes similar to those of catalytically competent kinases. However, pseudokinase pharmacological tractability and conformational space accessibility are poorly understood. Pseudokinases have only recently been suggested to adopt "inactive" conformations or interact with conformation-specific kinase inhibitors (e.g., type II compounds). In this work, the heavily substituted pseudokinase STRADα, which possesses a DFG → GLR substitution in the catalytic site that permits nucleotide binding while impairing divalent cation coordination, is used as a test case to demonstrate the potential applicability of conformation-specific, type II compounds to pseudokinase pharmacology. Integrated structural modeling is employed to generate a "GLR-out" conformational ensemble. Likely interacting type II compounds are identified through virtual screening against this ensemble model. Biophysical validation of compound binding is demonstrated through protein thermal stabilization and ATP competition. Localization of a top-performing compound through surface methylation strongly suggests that STRADα can adopt the "GLR-out" conformation and interact with compounds that comply with the standard type II pharmacophore. These results suggest that, despite a loss of catalytic function, some pseudokinases, including STRADα, may retain the conformational switching properties of conventional protein kinases.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/química , Trifosfato de Adenosina/química , Humanos , Domínios Proteicos , Estabilidade Proteica
4.
Cell Chem Biol ; 27(7): 770-772, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32679092

RESUMO

In this issue of Cell Chemical Biology, Pisa et al. (2020) find that haploid and diploid cells differentially develop resistance to the CENP-E inhibitor GSK923295. The results highlight the power of tumor cells to evade growth inhibition and potentially inform the design of next-generation CENP-E drugs to overcome resistance.


Assuntos
Diploide , Neoplasias , Compostos Bicíclicos Heterocíclicos com Pontes , Resistência a Medicamentos , Haploidia , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA