The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading.

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the RTK/MAPK pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of twelve KRAS G12C-mutant human non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1, PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.

Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein.

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT, resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

360° Video virtual reality exposure therapy for public speaking anxiety: A randomized controlled trial.

Public speaking anxiety (PSA) is a prevalent condition which is highly interrelated with social anxiety. PSA can be effectively treated with exposure therapy. Virtual reality exposure therapy (VRET) is increasingly being explored as a novel and cost-effective mode of treatment. No previous randomized controlled trial has examined whether stand-alone 360° video VRET is an effective intervention for treating PSA and interrelated disorder relevant fears. Further, studies have not explored whether 360° video content influences VRET outcomes. Participants with high PSA (n = 51) were randomly allocated to: 360° video VRET incorporating stimuli of audiences (360°Audience) (n = 17), 360° video VRET incorporating stimuli of empty rooms (360°Empty) (n = 16) and no treatment control (n = 18). Outcomes were measured over five time-points. Mixed ANOVA revealed a significant interaction between time and intervention group for PSA, social anxiety and fear of negative evaluation (FNE). Within-group analysis demonstrated there was a significant pre-intervention to post-intervention reduction across measures for both 360° video VRET groups: PSA 360°Audience (ηp2 = .90, p<.001), 360°Empty (ηp2 = .71, p < .001); social anxiety 360°Audience (ηp2 = .49, p=.002), 360°Empty (ηp2 = .39, p = .009); FNE 360°Audience (ηp2 = .59, p<.001), 360°Empty (ηp2 = .43, p = .006). Active intervention participants showed significant improvement from pre-intervention to 10-week follow-up on all measures. Findings illustrate that 360° video VRET is an efficacious way to significantly reduce PSA, social anxiety and FNE.