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1.
J Med Chem ; 63(5): 2013-2027, 2020 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-31059256

RESUMEN

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.


Asunto(s)
Antineoplásicos/química , Descubrimiento de Drogas/métodos , Mutación/genética , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Animales , Antineoplásicos/farmacología , Diseño de Fármacos , Descubrimiento de Drogas/tendencias , Humanos , Simulación del Acoplamiento Molecular/métodos , Simulación del Acoplamiento Molecular/tendencias , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
2.
J Med Chem ; 60(12): 4869-4881, 2017 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-28557458

RESUMEN

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.


Asunto(s)
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacología , Benzamidas/farmacología , Quinasas raf/antagonistas & inhibidores , Proteínas ras/genética , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Concentración 50 Inhibidora , Ratones , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Org Chem ; 73(22): 9151-4, 2008 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-18855482

RESUMEN

A new synthesis of 3,3'-bioxindoles is reported that is well suited for the preparation of unsymmetrical structures. In the key step, 3-hydroxy-3,3'-bioxindoles are constructed by Mukaiyama aldol reaction of 2-siloxyindoles with isatins. These tertiary carbinols are formed in high diastereoselectivities, with substitution at various positions of the isatin and the 2-siloxyindole being tolerated.


Asunto(s)
Aldehídos/química , Indoles/síntesis química , Isatina/química , Cetonas/química , Compuestos de Organosilicio/química , Indoles/química , Estereoisomerismo , Especificidad por Sustrato
5.
Org Lett ; 5(25): 4815-8, 2003 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-14653681

RESUMEN

A practical and efficient route to the CD spiroketal (C-16-C-28) of the spongistatins is reported. Two stereocenters are introduced from chiral building blocks with the remainder introduced by substrate-controlled transformations. The key beta-keto-1,3-dithiane intermediate is generated by a dithiol conjugate addition to an ynone and the 1,3-dithiane unit in the C-ring plays a key role in the spiroketalization and subsequent epimerization. The synthesis requires 24 steps, with a longest linear sequence of 19 steps in an overall yield of 14.5% (for the longest linear sequence). [reaction: see text]

6.
Org Lett ; 5(25): 4819-22, 2003 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-14653682

RESUMEN

The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]

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