Targeting CD148 for Antithrombotic Therapy: Functional and Molecular Evaluation of AKB-9778

El Badaoui, L., Jurcevic, S., Senis, Y. and Barr, A.J. 2026. Targeting CD148 for Antithrombotic Therapy: Functional and Molecular Evaluation of AKB-9778. Pharmacology Research & Perspectives. 14 (4) e70301. https://doi.org/10.1002/prp2.70301

TitleTargeting CD148 for Antithrombotic Therapy: Functional and Molecular Evaluation of AKB-9778
TypeJournal article
AuthorsEl Badaoui, L., Jurcevic, S., Senis, Y. and Barr, A.J.
Abstract

CD148 is the primary receptor-type protein tyrosine phosphatase (PTP) regulating platelet activation, and its inhibition has been proposed as a novel anti-thrombotic
strategy with potentially lower bleeding risk than current therapies. However, selective and potent inhibitors of CD148 are currently lacking. AKB-9778 (razuprotafib), a potent inhibitor of the closely related vascular endothelial-PTP
(VE-PTP), has also been reported to inhibit CD148. This study investigated the effect of AKB-9778 on in vitro whole-blood
thrombogenicity, examined the molecular basis of its interaction with the CD148 catalytic domain using molecular
docking, and assessed inhibitor selectivity with an in vitro phosphatase assay. In a total-thrombus formation analysis system (T-TAS), AKB-9778 partially inhibited thrombus formation, reducing AUC10 by 28%, without significantly affecting occlusion start time or occlusion time. The inhibitor did not alter collagen-stimulated CD62P platelet surface expression or PAC-1 binding to the activated integrin αIIbβ3. Molecular docking using CB-Dock predicted a binding configuration in which the phenylsulfamic acid group of AKB-9778 is orientated towards the catalytic cysteine, with additional conformations reflecting ligand flexibility.
Site-directed mutagenesis of Tyr1071, Gln1283, His1206, and Asn1073 to alanine reduced the inhibitory effect in phosphatase assays, supporting interaction with these residues. Notably, the IC50 of AKB-9778 against CD148 was approximately 300-fold higher than previously reported values, consistent with the wide variability across studies. Despite this reduced potency, these findings support the concept of CD148 inhibition as a potential anti-thrombotic
strategy and suggest that AKB-9778 may serve as a useful prototype for developing more selective and efficacious CD148 inhibitors.

KeywordsAKB-9778 | CD148 | molecular docking | platelets | PTPRJ | razuprotafib | receptor-type protein tyrosine phosphatase | thrombosis | T-TAS | VE-PTP
Article numbere70301
JournalPharmacology Research & Perspectives
Journal citation14 (4)
ISSN2052-1707
2052-1707
Year2026
PublisherWiley
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1002/prp2.70301
PubMed ID42538585
Web address (URL)http://dx.doi.org/10.1002/prp2.70301
Publication dates
Published01 Aug 2026

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