Discovery of an Atropisomeric PI3Kß Selective Inhibitor through Optimization of the Hinge Binding Motif.
ACS Med Chem Lett
; 11(6): 1236-1243, 2020 Jun 11.
Article
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| MEDLINE
| ID: mdl-32551006
ABSTRACT
A series of PI3Kß selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kß inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.
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MEDLINE
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ACS Med Chem Lett
Año:
2020
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Article
País de afiliación:
Estados Unidos