GSK2983559 / GSK - LARVOL DELTA

Receptor-interacting protein kinase 2 (RIPK2): Structural insights, pathophysiological roles, and medicinal chemistry advances in inhibitor design. (PubMed, Bioorg Chem) - "Clinically approved multikinase inhibitors-including ponatinib, gefitinib, and regorafenib-exhibit off-target RIPK2 inhibition, while selective compounds such as WEHI-345, GSK2983559, CSLP37, UH15-15, and thienopyrimidine derivatives represent key advances in selective blockade. Despite encouraging preclinical data, no RIPK2-specific inhibitor has yet achieved clinical approval due to safety and selectivity challenges. Continued structure-guided optimization, exploration of allosteric and degradation-based mechanisms, and integration into precision-medicine frameworks may ultimately enable safe and effective RIPK2-targeted therapies for inflammatory and autoimmune disorders, while the potential application in oncology remains under preclinical investigation."

Journal • Review • Breast Cancer • Immunology • Lung Cancer • Oncology • Targeted Protein Degradation • RIPK2 • XIAP

OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2. (PubMed, J Neuroinflammation) - "These findings suggested that RIP2 mediated cerebral ischemic lesion via stimulating inflammatory response, and OTUD1 ameliorated brain injury after ischemia through inhibiting RIP2-induced NF-κB activation by specifically cleaving K63-linked ubiquitination of RIP2."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Targeted Protein Degradation • Vascular Neurology • IL1B • IL6 • NFKBIA • OTUD1 • RIPK2 • TNFA

Discovery of a novel RIPK2 inhibitor for the treatment of inflammatory bowel disease. (PubMed, Biochem Pharmacol) - "Zharp2-1 exhibits significantly superior solubility compared to the non-prodrug form of the advanced RIPK2 inhibitor prodrug GSK2983559...Importantly, Zharp2-1 significantly ameliorates DNBS-induced colitis in rats and suppressed pro-inflammatory cytokine release in intestinal specimens from IBD patients. Collectively, our findings indicate that Zharp2-1 is a promising RIPK2 inhibitor with the potential to be further developed for IBD therapy."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • NF-κβ • NLRC5 • RIPK2

GSK2983559 First Time in Human Study (clinicaltrials.gov) - P1; N=58; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Apr 2019 ➔ Sep 2019; Trial primary completion date: Apr 2019 ➔ Sep 2019

Trial completion date • Trial primary completion date • Biosimilar • Immunology • Inflammation • Inflammatory Bowel Disease

GSK2983559 First Time in Human Study (clinicaltrials.gov) - P1; N=31; Terminated; Sponsor: GlaxoSmithKline; N=62 ➔ 31; Trial completion date: Jun 2020 ➔ Feb 2019; Suspended ➔ Terminated; Trial primary completion date: Jun 2020 ➔ Feb 2019; Terminated due to non clinical toxicology findings and reduced safety margins.

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • CRP • F2

GSK2983559 First Time in Human Study (clinicaltrials.gov) - P1; N=62; Suspended; Sponsor: GlaxoSmithKline; Recruiting ➔ Suspended

Clinical • Trial suspension

GSK2983559 First Time in Human Study (clinicaltrials.gov) - P1; N=62; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Sep 2019 ➔ Jun 2020; Trial primary completion date: Sep 2019 ➔ Jun 2020

Clinical • Trial completion date • Trial primary completion date