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1.
J Med Chem ; 65(18): 12427-12444, 2022 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-36066182

RESUMEN

Kinase fusions involving tropomyosin receptor kinases (TRKs) have been proven to act as strong oncogenic drivers and are therefore recognized as attractive therapeutic targets. We screened an in-house kinase-focused library and identified a promising hit compound with a unique tetracyclic scaffold. Compound 1 showed high TRK selectivity but moderate cell growth inhibitory activity as well as a potential risk of inducing CYP3A4. In this report, chemical modification intended to improve TRK inhibition and avoid CYP3A4 induction enabled us to identify an orally bioavailable, selective, and potent TRK inhibitor 7.


Asunto(s)
Neoplasias , Tropomiosina , Proliferación Celular , Citocromo P-450 CYP3A , Humanos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Receptor trkA
2.
J Med Chem ; 59(23): 10586-10600, 2016 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-27933954

RESUMEN

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3. The chemical modifications, which were guided by 3D-modeling analyses of the inhibitor and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3. In in vitro studies and xenograft models in mice, 8 shows antitumor activity against cancer cell lines that harbor genetically altered FGFRs. These results support the potential therapeutic use of 8 as a new anticancer agent.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Pirazoles/administración & dosificación , Pirazoles/química , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 21(6): 1795-801, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21316218

RESUMEN

The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.


Asunto(s)
Antineoplásicos/química , Benzamidas/química , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Oxazinas/química , Inhibidores de Proteínas Quinasas/química , Administración Oral , Regulación Alostérica , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Benzamidas/administración & dosificación , Benzamidas/farmacología , Humanos , Modelos Moleculares , Oxazinas/administración & dosificación , Oxazinas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología
4.
Bioorg Med Chem Lett ; 19(10): 2772-6, 2009 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-19362835

RESUMEN

CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.


Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Profármacos/síntesis química , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Camptotecina/sangre , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacocinética , ADN-Topoisomerasas de Tipo I/metabolismo , Perros , Haplorrinos , Humanos , Concentración de Iones de Hidrógeno , Irinotecán , Ratones , Ratones Desnudos , Profármacos/química , Profármacos/farmacocinética , Ratas , Inhibidores de Topoisomerasa I , Trasplante Heterólogo , Agua/química
5.
Bioorg Med Chem Lett ; 19(7): 2018-21, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19254843

RESUMEN

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.


Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacología , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Ratones , Relación Estructura-Actividad , Trasplante Heterólogo
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