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 receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (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 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer 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 and 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.

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.

Measuring the impact of therapy on medication use: data-linkage study.

BACKGROUND: The psychological therapies service (PTS) in the Northern Health and Social Care Trust, in Northern Ireland, provides therapies to adults with moderate or severe mental health difficulties. Psychometric outcomes data are routinely collected to assess if a patient demonstrates significant improvement in their main presenting problem area following therapy. The wider impact of therapy is not fully measured in the outcomes database as this would be disproportionately burdensome for both patient and therapist. The present study, to our knowledge, is the first to use data linkage to link patient therapy outcomes data with prescriptions data. AIMS: To widen our understanding of patient medication use before and after therapy. METHOD: Using Health and Care Number as a unique identifier, the Psychological Therapies Service - Routine Outcome Measurement Database (n = 3625) and data from 72 500 controls were linked with data from the Enhanced Prescribing Database (EPD). The EPD data were sourced from the Honest Broker Service. RESULTS: Key findings from the study were: (a) the odds of PTS clients using antipsychotics in the year before therapy were 25 times greater compared with controls (odds ratio (OR) = 24.53, 95% CI 20.16-29.84); (b) in the 1st year post discharge, PTS clients who clinically improved post therapy discharge were more likely than 'non-engagers' and 'non-improvers' to come off antianxiety medication (OR = 0.61, 95%, CI 0.38-0.98); and (c) therapy did not have an impact on antidepressant use. CONCLUSIONS: The results highlight the need for discussion between therapy services, GPs and psychiatry about whether more engagement and collaboration is needed to plan phased reduction in medication.

Environmental gradients predict the ratio of environmentally acquired carotenoids to self-synthesised pteridine pigments.

Carotenoids are important pigments producing integument colouration; however, their dietary availability may be limited in some environments. Many species produce yellow to red hues using a combination of carotenoids and self-synthesised pteridine pigments. A compelling hypothesis is that pteridines replace carotenoids in environments where carotenoid availability is limited. To test this hypothesis, we quantified concentrations of five carotenoid and six pteridine pigments in multiple skin colours and individuals from 27 species of agamid lizards. We show that environmental gradients predict the ratio of carotenoids to pteridines; carotenoid concentrations are lower and pteridine concentrations higher in arid environments with low vegetation productivity. Both carotenoid and pteridine pigments were present in all species, but only pteridine concentrations explained colour variation among species and there were no correlations between carotenoid and pteridine pigments with a similar hue. These results suggest that in arid environments, where carotenoids are likely limited, species may compensate by synthesising more pteridines but do not necessarily replace carotenoids with pteridines of similar hue.

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.

Red carotenoids and associated gene expression explain colour variation in frillneck lizards.

A long-standing hypothesis in evolutionary ecology is that red-orange ornamental colours reliably signal individual quality owing to limited dietary availability of carotenoids and metabolic costs associated with their production, such as the bioconversion of dietary yellow carotenoids to red ketocarotenoids. However, in ectothermic vertebrates, these colours can also be produced by self-synthesized pteridine pigments. As a consequence, the relative ratio of pigment types and their biochemical and genetic basis have implications for the costs and information content of colour signals; yet they remain poorly known in most taxonomic groups. We tested whether red- and yellow-frilled populations of the frillneck lizard, Chlamydosaurus kingii, differ in the ratio of different biochemical classes of carotenoid and pteridine pigments, and examined associated differences in gene expression. We found that, unlike other squamate reptiles, red hues derive from a higher proportion of ketocarotenoids relative to both dietary yellow carotenoids and to pteridines. Whereas red frill skin showed higher expression of several genes associated with carotenoid metabolism, yellow frill skin showed higher expression of genes associated with steroid hormones. Based on the different mechanisms underlying red and yellow signals, we hypothesize that frill colour conveys different information in the two populations. More generally, the data expand our knowledge of the genetic and biochemical basis of colour signals in vertebrates.

Recognition of proteins by crystallization patterns in an array of reporter solution microdroplets.

A new technique is described for specific recognition of protein analytes by observing protein-induced changes in the drying/crystallization patterns (DCP) of an array of microdroplets containing solutions of different reporter substances. Recognition is based on a difference in interaction of the protein analyte crystalline elements (planes, edges, defects, etc.) in the growing reporter crystals. Using a set of natural L-amino acids as reporters and denoting the amino acid solutions displaying substantial protein-induced changes in the DCP as "1" and those that show no or small changes as "0", a digital binary code was determined for several proteins at multiple concentrations. It was demonstrated that globular proteins can be reliably identified using this code as a "signature" when only 2-100 ng of protein was added to amino acid microdroplets.