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Autism spectrum disorders (ASDs) are diagnosed in 1/100 children worldwide, based on two core symptoms: deficits in social interaction and communication, and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR; vasopressin V 1A and V 1B ; metabotropic glutamate mGlu 5 and mGlu 7 ; GABA B2 ; dopamine D 1 , D 2 and D 3 ; serotoninergic 5-HT 1B ; β 2 -adrenoceptor; cholinergic M 3 ; adenosine A 2A and A 3 ; angiotensin AT 2 ; cannabinoid CB 1 ; chemokine CX 3 CR1; orphan GPR37 and GPR85; and olfactory OR1C1, OR2M4, OR2T10 and OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, as well as 5-HT 2A and 5-HT 7 , for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopoeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight D 2 , 5-HT 2A , CB 1 , OTR and V 1A as the more promising targets for ASD. We discuss that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD. Their therapeutic potential has only begun as multiple GPCRs could mitigate ASD., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib., Methods: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics., Results: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg., Conclusions: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings., Gov Identifier: NCT01425008., (© 2023. The Author(s).)