Clinically Anchored GPCR Drug Discovery: Translational Lessons from Success, Failure, and Post-Approval Reassessment
- 1Department of Physiology, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
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.
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BibTeX
@article{seo2026clinically,
title = {{Clinically Anchored GPCR Drug Discovery: Translational Lessons from Success, Failure, and Post-Approval Reassessment}},
author = {Yohan Seo and Joohan Woo},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/ph19101510},
url = {https://europepmc.org/article/PMC/PMC13708073},
note = {CC BY},
}
RIS
TY - JOUR
TI - Clinically Anchored GPCR Drug Discovery: Translational Lessons from Success, Failure, and Post-Approval Reassessment
AU - Yohan Seo
AU - Joohan Woo
PY - 2026
DA - 2026/09/01
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101510
UR - https://europepmc.org/article/PMC/PMC13708073
AB - 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.
SN - 1424-8247
ER -