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. 2022 Dec 13;13(3):598–615. doi: 10.1158/2159-8290.CD-22-0968

Figure 3.

Figure 3. NVL-520 selectively inhibits ROS1 while avoiding phospho-TRKB inhibition. A, Activity of ROS1 TKIs at inhibiting viability of ROS1-fusion cell lines or TRKB phosphorylation (pTRKB) in BDNF-stimulated Ba/F3 TRKB cells. TRKB phosphorylation was measured with AlphaLISA assay and was not normalized to total TRKB. Top, Dose–response curve overlays highlighting the differential activity of ROS1 TKIs against ROS1, ROS1 G2032R, and pTRKB. The green arrow denotes the separation between ROS1 inhibition and TRKB inhibition of NVL-520. Curves are fitted to composite data from multiple repeats (n ≥ 2), with individual data points not shown. Bottom, Geometric means of IC50 (nmol/L) with standard deviation and number of repeats are provided. B, Selectivity window analysis showing the relative preferences of each TKI for ROS1 or ROS1 G2032R over TRKB. Numerical selectivity values are indicated alongside the bars and are calculated from IC50 values in Fig. 3A.

NVL-520 selectively inhibits ROS1 while avoiding pTRKB inhibition. A, Activity of ROS1 TKIs at inhibiting viability of ROS1 fusion cell lines or pTRKB in BDNF-stimulated Ba/F3 TRKB cells. pTRKB was measured with the AlphaLISA assay and was not normalized to total TRKB. Top, dose–response curve overlays highlighting the differential activity of ROS1 TKIs against ROS1, ROS1 G2032R, and pTRKB. The green arrow denotes the separation between ROS1 inhibition and TRKB inhibition of NVL-520. Curves are fitted to composite data from multiple repeats (n ≥ 2), with individual datapoints not shown. Bottom, geometric means of IC50 (nmol/L) with standard deviation and number of repeats are provided. B, Selectivity window analysis showing the relative preferences of each TKI for ROS1 or ROS1 G2032R over TRKB. Numerical selectivity values are indicated alongside the bars and are calculated from IC50 values in A.