RESUMO
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96â h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology inâ vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
Assuntos
Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dipeptídeos/química , Dipeptídeos/farmacocinética , Dipeptídeos/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Estrutura Molecular , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, Proteolysis Targeting Chimeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.
Assuntos
Benzotiazóis/metabolismo , Isoquinolinas/metabolismo , Oligopeptídeos/metabolismo , Proteólise/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteína bcl-X/antagonistas & inibidores , Benzotiazóis/química , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ligação Proteica , Proteína bcl-X/química , Proteína bcl-X/metabolismoRESUMO
A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.