RESUMEN
Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.
Asunto(s)
Neoplasias , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Mutación , Progresión de la Enfermedad , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor Tipo 3 de Factor de Crecimiento de FibroblastosRESUMEN
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/uso terapéutico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Ácidos Ftálicos/química , Ácidos Ftálicos/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Descubrimiento de Drogas , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Ratones , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias/patología , Ácidos Ftálicos/farmacocinética , Ácidos Ftálicos/farmacologíaRESUMEN
PURPOSE: The primary objective of this study was to compare uptake and distribution of the commercially available formulation of 0.2% olopatadine and the newly developed 0.77% olopatadine hydrochloride ophthalmic solution formulation with improved solubility following a single (30 µL), bilateral topical ocular dose in male New Zealand white rabbits. METHODS: Each animal received a single 30-µL topical ocular dose (0.2% olopatadine or 0.77% olopatadine hydrochloride ophthalmic solution) to the right (OD) eye followed by the left (OS) eye for a total dose of 60 µL. Olopatadine concentrations were measured in ocular tissues (cornea, bulbar, conjunctiva, choroid, iris-ciliary body, whole lens, retina), aqueous humor, and plasma at prespecified time points over 24 h using a qualified liquid chromatography coupled with mass spectrometry (LC-MS/MS) analytical method. RESULTS: Olopatadine was absorbed into the eye and reached maximal levels (Cmax) within 30 min (0.5 h) to 2 h (Tmax) in ocular tissues and plasma for both treatment groups, except for the lens in which the Tmax was 4 h in the 0.2% olopatadine group and 8 h in the 0.77% olopatadine hydrochloride group, respectively. Tissues associated with the site of dosing, that is, the conjunctiva and cornea, had the highest concentrations of olopatadine in both the 0.2% olopatadine (609 and 720 ng/g) and 0.77% olopatadine hydrochloride (3,000 and 2,230 ng/g) dose groups. The greatest differences between 0.2% olopatadine and 0.77% olopatadine hydrochloride were associated with the overall duration and level of ocular exposures. CONCLUSIONS: The newly developed 0.77% olopatadine hydrochloride ophthalmic solution formulation resulted in a higher and more prolonged olopatadine concentration in the target tissue, that is, conjunctiva compared to the commercial formulation of 0.2% olopatadine ophthalmic solution.