Clinically Anchored GPCR Drug Discovery: Translational Lessons from Success, Failure, and Post-Approval Reassessment
Year: 2026
Type: review
Abstract: Background/Objectives: G protein-coupled receptors are a productive drug target family, yet clinical performance varies widely across rare, immune-mediated, pain, and thromboinflammatory diseases. We aimed to construct an explicit, stage-gated framework that makes translational prioritisation auditable and to examine whether it distinguishes clinically successful from unsuccessful programmes. Methods: This narrative, clinically anchored review included programmes with a stated human-disease rationale, Phase 2 or later clinical experience or a regulatory decision, and publicly accessible primary or regulatory documentation; evidence was considered through 7 August 2026. The cases spanned rare disease, immune-mediated inflammation, pain, and thromboinflammation. Thirteen programmes were reviewed, and eleven were entered into a retrospective five-axis scorecard covering human-disease anchoring, receptor pharmacology, modality and pharmacokinetic/pharmacodynamic feasibility, biomarker-to-endpoint readiness, and durability. Each axis was scored 0–2, weighted to 100 points, and subject to predefined hard-stop rules. Results: Established successes scored 80–100 points, whereas failed programmes scored 30–48. PAR4 scored 57.5 and therefore fell in the stop-and-rework band; avacopan scored 80 before approval but now triggers an Axis 5 hard stop. Equal weighting preserved the classifications of established successes and hard-stop failures but shifted PAR4 to 60.0, demonstrating sensitivity of a borderline programme to the weighting scheme. The scorecard localized failures mainly to redundancy, biomarker–endpoint disconnect, or durability/evidence-integrity gates. Conclusions: The framework is an explicit prioritisation aid, not an externally validated predictive model. Its main value is to identify missing evidence and non-compensable weaknesses; prospective independent validation, including inter-rater reliability testing, is required before portfolio use.
Source: Pharmaceuticals
DOI: 10.3390/ph19101510
Authors: Yohan Seo, Joohan Woo
Institutions: Dongguk University, Dongguk University WISE
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funders: Dongguk University, Ministry of Agriculture, Food and Rural Affairs, Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries, National Research Foundation of Korea, Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry
OpenAlex ID: W7214126620