RO8994

RO8994 (Compound 4) is an orally active, highly potent and selective spiroindolinone p53-MDM2 inhibitor with an IC₅₀ value of 5 nM (HTRF binding assays) and 20 nM (MTT proliferation assays). RO8994 induces up-regulation of p53 expression and Apoptosis in wild-type p53 cancer cells. RO8994 also inhibits tumor growth in the tumor xenograft model^[1][2][3]. In Vitro: RO8994 dose-dependently and non-genotoxically induces p53 stabilization, cell cycle arrest and Apoptosis in tumor cells retainingwt p53^[3].

Activity Results for RO8994 in a Biochemical Binding Assay and Human Cancer Cell Proliferation Assays^[1][2][3]<

compd	HTRF IC50 (nM)	SJSA IC50 (μM)	SW480 IC50 (μM)
RO8994	5	0.013	5.19

Antiproliferative Activity of RO8994 in Human Cancer Cell lines^[1][2][3]<

compd	MTT IC50 (μM)	selectivity
RO8994	0.02	312

In Vivo: RO8994 inhibits tumor growth in human SJSA1 tumor xenografts models^[3].

Human Liver Microsomal Stability and Mean Single Dose PK Parameters of RO8994 in C57 Male Mice by Oral and IV Dosing^[1][2][3]<

compd	HLM_CL (mL/min/kg)	PO dose (mg/kg)	PO AUC/dose (μg·hr/mL/mg/kg)	PO Cmax (μg/mL)	IV dose (mg/kg)	CL (mL/min/kg)	t1/2 (h)	F (%)
RO8994	7.5	25	3.7	5.8	0.64	5.8	7.1	92