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ConspectusNearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRAS

Researchers have suggested that overconsumption of food, alcohol, and drugs could be explained by chronically elevated approach tendencies to rewarding but unhealthy stimuli. Here, we use the example of food to show that dysregulated rather than chronically elevated approach tendencies are associated with negative health outcomes. To this end, we developed a new smartphone-based paradigm to measure dynamic changes in food approach tendencies outside the laboratory (piloted with N = 48). We demonstrated in three pre-registered experiments (total N = 367) that food approach tendencies decrease from before to after people have eaten. We further show that in overweight and obese participants, these dynamics are disrupted, as their food approach tendencies increase rather than decrease after meals. In addition to showing these effects based on traditional reaction time-based food approach tendencies, we also demonstrate these patterns in a novel measure of response force—a measure that has long been used to study motivation in animals but has received little attention in humans. Together, our findings suggest that both reaction-time based, and force-based approach tendencies change dynamically in accordance with people’s need states and that disruptions in these dynamics are associated with negative health outcomes, such as overweight and obesity.

Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non–small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC.Significance:No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601

Supplementary Tables (S1-6) and Figures (S1-6)

Self-regulation, the ability to guide behavior according to one’s goals, plays an integral role in understanding loss of control behaviors a pertinent example being substance use disorders (SUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors often occur, namely in real life situations outside the laboratory. Moreover, lab-based experimental tasks are criticized for poor test–retest reliability and a lack of construct validity. These concerns might in part explain why ecological validity of experimental measures—their ability to predict real-life behavior—is low. To address these shortcomings, we assessed the reliability and construct validity of four smartphone-based experimental tasks designed to measure cognitive control and decision-making. To facilitate future clinical applicability we recruited a large (N=488) sample of individuals with SUD. Joint modeling of measurement sessions increased the reliability of task measures from moderate to good and often excellent levels. In line with theories of cognitive control and motivation, three latent factors reflecting cognitive control and decision-making in the context of gains and losses best described the data. As proof of concept, we show that a latent cognitive control score based on joint modeling, yielded stronger correlations with drinking behavior than single task scores based on separate modeling. These findings indicate that in individuals with SUD, smartphone-based ambulatory experimental assessments can reliably index functions of cognitive control and decision-making, with plausible construct validity. Our findings provide evidence for rich possibilities arising from longitudinal experimental studies in SUD as well as in psychiatry, neuroscience, and psychology more generally.

Aims/hypothesis. Pharmacological conditioning, where an association is formed between a drug and a conditioned stimulus (CS, e.g., smell), can influence physiological processes. Evidence exists that it is possible to condition insulin effects in animals and healthy humans but it is unclear whether these effects can be observed in patients as well. The aim of this study was to investigate the effects of pharmacological conditioning with intranasal insulin on blood glucose, insulin, c-peptide, hunger and memory in patients with diabetes type-2 and age- and sex-matched healthy controls. Exploratively, we examined sex differences in these effects. We hypothesized that conditioning with insulin would trigger endogenous insulin release, decrease blood glucose and hunger, and improve memory. Methods. In a randomized double-blind controlled trial, thirty-two patients with diabetes type-2 (17 males, mean age=68.8, SD=11.86) and thirty-two healthy controls (17 males, mean age=67.8, SD=6.12) were randomly assigned to a conditioned or a control group. On day 1, participants in the conditioned group received 6 administrations of 20 units of intranasal insulin together with a CS (smell of rosewood oil) while the control group received a placebo with the CS. On day 2, participants in both groups received a placebo spray with the CS. Glucose, insulin and c-peptide were repeatedly measured in blood on both days. Hunger was measured with a self-report question, a mobile approach-avoidance task and a taste test. Memory was measured with an auditory verbal learning test.Results. Intranasal insulin prevented the drop of glucose levels in patients but not in healthy controls (B=0.03, SE=0.02, p=0.027), and decreased C-peptide levels in healthy controls but not patients (B=0.01, SE=0.001, p=0.008). Conditioned insulin effects also prevented the drop of blood glucose levels but only in male participants (for both healthy and patient groups) (B=0.001, SE=0.0003, p=0.024). Moreover, conditioning significantly decreased hunger in healthy participants (B=0.31, SE=0.09, p< 0.001). No effects of intranasal insulin or conditioning were found on insulin, approach-avoidance tendencies, calories eaten and memory. Conclusions/interpretation. Our study provides further evidence that conditioning with intranasal insulin might modify blood glucose levels and decrease hunger and that its effects differ depending on health status and sex. The unexpected direction of intranasal insulin effects on blood glucose might potentially be explained by age as our study population was older than participants from previous research. Conditioning with intranasal insulin might be beneficial for groups suffering from intensive hunger, but seems not be particularly suitable for blood glucose reduction. Diabetes type-2 patients might benefit from conditioning with glucose lowering drugs.

In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy.