RAD001 and BEZ235 synergistically inhibit growth of 786-O cells <i>in vitro</i> and <i>in vivo</i>.

<p>786-O cells (PTEN and VHL-deficient renal cell carcinoma) were treated for 72 h with different doses of RAD001 and/or BEZ235, inhibition of cell viability was measured using CellTiter-Glo (A), and Chalice software was used to calculate excess inhibition over Loewe additivity for each RAD001 and/or BEZ235 dose combination (B). Data values represent the mean from 3 wells. Mice bearing 786-O xenografts were dosed daily for 3 weeks with RAD001, BEZ235, or the combination of the two compounds. Mean tumor volumes were measured and are plotted as a function of time (C).</p

The combination of RAD001 and BEZ235 can induce cell death in SK-BR-3 cells.

<p>SK-BR-3 cells were treated with RAD001 and/or BEZ235 at the indicated concentrations and electric impedance was measured every 15 minutes with the xCELLigence system (A). Cell index values were calculated and plotted as a function of time. The time of compound addition is indicated with an arrow, and the continuous vertical line indicates the normalization point. Each data point represents the average of 3 wells ±1 SD. SK-BR-3 cells were treated for 48 h with the indicated doses of RAD001 and/or BEZ235, or for 3 h with Staurosporin. Cells were lysed and endogenous proteins visualized by western blot analysis (B). SK-BR-3 cells were treated for 24 h with the indicated doses of RAD001 and/or BEZ235. Gene expression changes were quantified by microarray analysis, computed as log2 relative ratios (treatment/vehicle control), and subjected to hierarchical clustering along the gene probe axis (C).</p

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with <i>MTAP</i>-Deleted Cancers

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood–brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with <i>MTAP</i>-Deleted Cancers

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood–brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss