RESUMEN
Replacement of one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 (1) with sulfonamide containing substituents produced a new class of active and potent PI3Kα inhibitors. Solubility issues prevented all but the 6-amino derivative 17 from being evaluated in vivo, but the clear activity of this compound demonstrated that this class of PI3K inhibitor shows great promise.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Triazinas/química , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Humanos , Estructura Molecular , Solubilidad , Sulfonamidas/química , Triazinas/farmacologíaRESUMEN
Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Piridinas/síntesis química , Piridinas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Piridinas/química , Relación Estructura-ActividadRESUMEN
In the crystal structure of the title compound, C(16)H(16)O(6), a pair of naphthoquinone rings are linked via O-Hâ¯O-C hydrogen bonds in a nearly orthogonal arrangement. This dimeric unit is linked to a neighbouring dimer by π-π stacking inter-actions between the naphthoquinone rings, where the distance between the mean plane of the naphtoquinone backbones is 3.468â Å, and O-Hâ¯O-C hydrogen bonds.
RESUMEN
Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3K isoforms and mTOR, displaying preferential activity for PI3Kα and sparing of PI3Kδ relative to the other inhibitors, while showing less off-target activity than the clinical inhibitors in a panel of 442 kinases. The major metabolites of SN32976 were also potent PI3K inhibitors with similar selectivity for PI3Kα as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3K inhibitors in cellular assays, inhibiting pAKT expression and cell proliferation at nM concentrations, and in animal models, inducing a greater extent and duration of pAKT inhibition in tumors than pictilisib, dactolisib and omipalisib at similarly tolerated dose levels and inhibiting tumor growth to a greater extent than dactolisib and ZSTK474 and with similar efficacy to pictilisib and omipalisib. These results suggest that SN32976 is a promising clinical candidate for cancer therapy with enhanced kinase selectivity and preferential inhibition of PI3Kα compared to first generation pan PI3K inhibitors, while retaining comparable anticancer activity.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Glucosa/metabolismo , Humanos , Masculino , Ratones , Fosforilación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
[reaction: see text] The synthesis of the fused aromatic spiroketal core of gamma-rubromycin is described via addition of an aryl acetylide fragment to an aryl acetaldehyde fragment. In turn, the aryl acetylene precursor was readily prepared with use of a Sonogashira reaction.