IC50:The IC50 of GNF-7is 0.005, 0.001, and 0.008 µM in Colo205, SW620, and TrkC-Ba/F3 cells, respectively.
GNF-7 is the type-II inhibitor of T315I-Bcr-Abl [1]. BCR-ABL, constitutively activated tyrosine kinase, is an oncogene associated with chronic myelogenous leukemia (CML) and some cases ofacute lymphocytic leukemia in humans.
In vitro:GNF-7 showed excellent growth inhibitory activity against some human cancer cells. The IC50 of GNF-7is 0.005, 0.001, and 0.008 µM when tested in Colo205, SW620, and TrkC-Ba/F3 cell line, respectively.GNF-7 showed little effect on HEK293T cells, a normal cell line [1].After treated for 24h (7.5mg/kg QD or 15 mg/kg QD), GNF-7 significantly decreaseddisease burden in mice and prolonged overall survival compared to vehicle-controls [2].
In vivo:In acute myelogenous leukemia and lymphoblastic leukemia models, GNF-7 potently and selectively inhibited NRAS-dependent cells [2]. In theT315I-Bcr-Abl-Ba/F3 cell line bioluminescent xenograft mouse model,oral administration of GNF-7 with 10or20mg/kgexhibited significant efficacy against T315I-Bcr-Abl without appreciable toxicity [1].
References:
[1].Choi H G, Ren P, Adrian F, et al. A type-II kinase inhibitor capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl[J]. Journal of medicinal chemistry, 2010, 53(15): 5439-5448.
[2].Nonami A, Sattler M, Weisberg E, et al. Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach[J]. Blood, 2015, 125(20): 3133-3143.