ABSTRACT
Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TRKA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 µM). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TRKA/B/C, TRKA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers.
Subject(s)
Drug Design , Drug Resistance, Neoplasm/drug effects , Mutation , Receptor, trkA/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Drug Resistance, Neoplasm/genetics , Humans , Male , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Receptor, trkA/genetics , Thiazoles/administration & dosage , Thiazoles/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
The present study was carried out on a number of 16 skulls of adult male domestic donkeys. Craniometric measurements for 40 different parts of the skulls were made. All investigated features were expressed as Mean±SD. Cephalic indices and ratios were calculated by using the investigated features. The craniometric measurements and cephalic indices had been compared with those of local horses and ponies. A skull length of 443.07±53.57 mm and a maximum zygomatic width of 169.09±17.64 mm were obtained. The size of donkey skull was between those of local horses and ponies. A skull index of 38.23±0.85, a cranial index of 45.01±2.83 and a facial index of 67.80±3.79 were obtained. Cranial index and skull index were found to be close in value to that of local horses and ponies. The results of this study revealed that donkey had a longer nose than local horse and pony, and the difference of skull length in the three species accounted for the facial length difference.
Se realizó un estudio sobre una serie de 16 cráneos pertenecientes a burros domésticos adultos, de sexo masculino. Se hicieron mediciones craneométricas en 40 partes diferentes de las muestras. Todas las características investigadas se expresaron como media ± desviación estándar, calculándose índices y proporciones cefálicas. Se compararon las mediciones craneométricas e índices cefálicos con los de caballos y ponis de la zona. La longitud del cráneo obtenida fue de 443,07±53,57 mm, con una anchura máxima del hueso cigomático de 169,09±17,64 mm. El tamaño del cráneo del burro se ubicó entre el de los caballos y los ponis locales. Se obtuvo un índice de cráneo de 38,23±0,85, un índice craneal de 45,01±2,83 y un índice facial de 67,80±3,79. Los índices craneal y de cráneo encontrados fueron cercanos a los valores correspondientes a los caballos y ponis locales. Los resultados de este estudio revelaron que el burro tenía una nariz más larga que el caballo y el poni. Además, la diferencia en longitud del cráneo en las tres especies representa la diferencia de longitud facial.