Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation.
Eur J Med Chem
; 191: 112143, 2020 Apr 01.
Article
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| MEDLINE
| ID: mdl-32078865
ABSTRACT
Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC50 = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI50 value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kß. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.
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1
Base de datos:
MEDLINE
Asunto principal:
Compuestos de Espiro
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Fosfatidilinositol 3-Quinasas
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Inhibidores de las Quinasa Fosfoinosítidos-3
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Antineoplásicos
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En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article