Cenisertib

Cenisertib (AS-703569) is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT, STAT5 and FLT3. Cenisertib induces major growth-inhibitory effects by blocking the activity of several different molecular targets in neoplastic mast cells (MC)[1]. Cenisertib inhibits tumor growth in xenograft models of pancreatic, breast, colon, ovarian, and lung tumors and leukemia[2].

Signaling Pathways >> Epigenetics >> Aurora Kinase

Signaling Pathways >> Stem Cell/Wnt >> STAT

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Aurora Kinase

Signaling Pathways >> JAK/STAT Signaling >> STAT

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Bcr-Abl

Signaling Pathways >> PI3K/Akt/mTOR >> Akt

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> FLT3

Aurora-A

Aurora-B

ABL1

Akt

STAT5

Cenisertib (AS-703569) (1-1000 nM; for 48 hours) induces dose-dependent inhibition of proliferation in primary neoplastic mast cells (MC) [1]. Cenisertib (5-100 nM; for 24 hours) induces a substantial G2/M cell cycle arrest at low nanomolar concentrations in all MC lines[1]. Cenisertib (1-1000 nM; for 24 hours)induces apoptosis in HMC-1.1, HMC-1.2, C2, and NI-1 cells in a dose-dependent manner[1]. Cenisertib (5-500 nM; for 24 hours) induces cleavage of caspase 3 in both HMC-1 sub-clones as well as in C2 and NI-1 cells[1]. Cell Proliferation Assay[1] Cell Line: HMC-1.1, HMC-1.2, ROSAKIT WT, ROSAKIT D816V and MCPV-1.1 mast cells Concentration: 1, 5, 10, 50, 100, 500, 1000 nM Incubation Time: 48 hours Result: Induced dose-dependent inhibition of proliferation in primary neoplastic MC. Cell Cycle Analysis[1] Cell Line: HMC-1.1, HMC-1.2, C2 and NI-1 cells Concentration: 5, 10, 50, 100 nM Incubation Time: 24 hours Result: Induced a substantial G2/M cell cycle arrest at low nanomolar concentrations in all MC lines. Apoptosis Analysis[1] Cell Line: HMC-1.1, HMC-1.2, C2 and NI-1 cells Concentration: 1, 5, 10, 50, 100, 500, 1000 nM Incubation Time: 24 hours Result: Induced apoptosis in HMC-1.1, HMC-1.2, C2, and NI-1 cells in a dose-dependent manner. Western Blot Analysis[1] Cell Line: HMC-1.1, HMC-1.2, C2 and NI-1 cells Concentration: 50, 100, 500 nM Incubation Time: 24 hours Result: Induced cleavage of caspase 3 in both HMC-1 sub-clones as well as in C2 and NI-1 cells.

Cenisertib (AS-703569) (orally; 7 or 10 mg/kg/day; for 3 days) significantly suppresses tumor growth. Animal Model: Female CB17 Severe Combined Immunodeficiency (SCID) mice bearing NCI-MDR tumors[2] Dosage: 7 and 10 mg/kg Administration: Orally; daily; for 3 days Result: Suppressed significantly tumor growth.

[1]. Peter B, et al. Drug-induced inhibition of phosphorylation of STAT5 overrides drug resistance in neoplastic mast cells. Leukemia. 2018 Apr;32(4):1016-1022.

[2]. McLaughlin J, et al. Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin Oncol. 2010 Jan;136(1):99-113.