GSK2982772 / GSK - LARVOL DELTA

Receptor interacting protein kinase 1 as a potential therapeutic target in inflammatory bowel disease: biological rationale and emerging clinical evidence. (PubMed, Expert Opin Investig Drugs) - "GSK2982772 did not demonstrate convincing efficacy, whereas clinical efficacy data for newer RIPK1 inhibitors, including ABBV-668 and eclitasertib, have not yet been reported. RIPK1 remains a compelling but clinically unvalidated target in IBD. Future progress will depend on improved patient selection, confirmation of mucosal target engagement, and better recognition of patients in which RIPK1 signaling is a key driver."

Journal • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Ulcerative Colitis • RIPK1 • TNFA

Structure-based optimization of GSK2982772-derived RIPK1 inhibitors reveals the dispensability of the methylene linker and identifies a potent anti-necroptosis candidate for further optimization. (PubMed, Eur J Med Chem) - "RIPK1 inhibitors based on the 5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide scaffold have demonstrated potent anti-inflammatory activity, and two representatives, GSK2982772 and GSK3145095, advanced into Phase II clinical trials. Furthermore, W-1 displayed lower cytotoxicity and reduced predicted interactions with more than 70 toxicity-associated targets, suggesting a potentially improved safety profile. Although its pharmacokinetic properties remain to be further optimized, W-1 represents a promising starting point for the development of next-generation RIPK1 inhibitors."

Journal • Immunology • Inflammation • Systemic Inflammatory Response Syndrome • CDK7 • RIPK1

Inhibition of RIPK1/RIPK3-MLKL inflammatory signaling pathway activation attenuates preterm birth. (PubMed, Cell Death Discov) - "RIPK1 expression was modulated via shRNA-mediated knockdown or pharmacological inhibition with GSK2982772 and Nec-1...Notably, in vivo treatment with Nec-1 ameliorated LPS-induced placental damage. Collectively, our findings demonstrate that RIPK1 drives inflammation and necroptosis in PTB through RIPK3-MLKL activation, suggesting that targeting RIPK1 may represent a promising therapeutic strategy for inflammation-associated preterm labor."

Journal • Inflammation • IL1B • IL6 • RIPK1 • TNFA

Treatment of Inflammatory Bowel Disease with Drugs Targeting PANoptosis: A Comprehensive Review. (PubMed, Biomedicines) - "However, clinical translation remains challenging; for instance, while targeting pyroptosis via IL-1/IL-18 (Anakinra) showed promise in theory, clinical results in IBD have been disappointing. Furthermore, RIPK1 inhibitors such as GSK2982772 have failed to meet primary endpoints in Phase 2 trials. PANoptosis is a "hot" therapeutic target, but successful treatment likely requires combination therapies or "PANoptosome" specific modulators rather than single-pathway inhibition."

Journal • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • ADAR • IGF2BP1 • IL18 • RIPK1 • ZBP1

Pharmacological and Mechanism Study of a New RIPK1 Inhibitor Via Necroptosis to Treat Hemophagocytic Lymphohistiocytosis (ASH 2024) - "PI/Hoechst results showed that SKLB-Z30 monotherapy inhibited necroptosis at low concentrations (10 nM), significantly outperforming GSK2982772...SKLB-Z30 monotherapy and combination therapy with dexamethasone significantly reduced liver and spleen size, improved anemia, increased platelet counts, reduced serum ferritin, and decreased levels of TNFα, IL-6, and other cytokines. Conclusion : The novel RIPK1 inhibitor SKLB-Z30 demonstrated effective therapeutic action against HLH in both in vivo and in vitro experiments. RIPK1 inhibitors represent a promising new approach for the clinical treatment of HLH patients."

Anemia • CNS Disorders • Hematological Disorders • Hemophagocytic lymphohistiocytosis • Hepatology • Immunology • Infectious Disease • Liver Failure • Rare Diseases • Septic Shock • Thrombocytopenia • CDK7 • IL6 • MLKL • RIPK1 • TNFA

RIPK1 in Diffuse Glioma Pathology: From Prognosis Marker to Potential Therapeutic Target. (PubMed, Int J Mol Sci) - "Transcriptomic studies were carried out using USC Xena and R, while in vitro assays were performed with the glioblastoma human cell line U251 and the commercial RIPK1 inhibitor GSK2982772...To further characterize the role of RIPK1 in DG, the effects of the RIPK1 inhibitor were evaluated, alone or combined with cisplatin, on glioblastoma cell proliferation and apoptosis. The combined treatments effectively reduced cell proliferation and increased apoptosis. The overexpression of RIPK1 was associated with a poor prognosis for DG, suggesting that RIPK1 plays a critical role in glioma pathogenesis and should be considered in therapeutic decision-making."

Biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • RIPK1

The Involvement of RIPK1 in Alopecia Areata. (PubMed, Int J Mol Sci) - "RIPK1 inhibitors (i.e., Necrostatin-1s and GSK2982772) delayed the onset of AA in the mouse model and reduced the numbers of DCs and CD8+ T cells in AA skin. The RIPK1 inhibitors also increased the hair length in a mouse hair organ culture mimicking AA. Collectively, these results suggest that RIPK1 is involved in AA onset via modulating immune cells, and RIPK1 inhibitors could prevent AA onset."

Journal • Alopecia • Immunology • CD8 • RIPK1

RIPK1 expression and inhibition in tauopathies: implications for neuroinflammation and neuroprotection. (PubMed, Front Neurosci) - "Furthermore, we investigated the potential of using a RIPK1 inhibitor, known as GSK2982772, in a mouse model as a novel treatment strategy for FTD...However, this RIPK1 inhibitor failed to protect against the neurodegeneration caused by elevated TAUP301L levels in the hippocampal region. These results suggest that although inhibiting RIPK1 activity may help reduce TAU-related astrogliosis in the brain, the complexity of the inflammatory pathways involved could explain the absence of neuroprotective effects against TAU-induced neurodegeneration."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Inflammation • Movement Disorders • Progressive Supranuclear Palsy • RIPK1

Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. (PubMed, Dermatol Ther (Heidelb)) - P1 | "Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements."

Clinical • Journal • Dermatology • Immunology • Inflammation • Psoriasis • RIPK1

Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors. (PubMed, Bioorg Med Chem Lett) - "Herein we used GSK2982772 as our starting point in our discovery campaign...The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective."

Journal • Inflammation • CDK7 • RIPK1

Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities. (PubMed, J Med Chem) - "GSK2982772, developed by GlaxoSmithKline (GSK), became the world's first RIP1 inhibitor approved for clinical research in 2014...The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents."

Journal • Review • CNS Disorders • Immunology • Inflammation • Oncology • RIPK1

Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology. (PubMed, Pharm Res) - P1 | "The DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018)."

Journal • RIPK1

Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis. (PubMed, Angew Chem Int Ed Engl) - "The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 ( ZB-R-55 ) which is about 10-fold more potent than GSK2982772 , and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate."

Journal • Immunology • Infectious Disease • Inflammation • Septic Shock • Systemic Inflammatory Response Syndrome • RIPK1

A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - P1; N=29; Completed; Sponsor: GlaxoSmithKline; Active, not recruiting ➔ Completed; Phase classification: P1/2 ➔ P1

Clinical • Phase classification • Trial completion • Dermatology • Immunology • Psoriasis

A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - P1/2; N=29; Active, not recruiting; Sponsor: GlaxoSmithKline; N=21 ➔ 29

Clinical • Enrollment change • Dermatology • Immunology • Psoriasis

Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma. (PubMed, Antioxidants (Basel)) - "The present study examined whether necrostatin-1 could interrupt ferroptosis induced by system xc- inhibitors (sulfasalazine and erastin) and a glutathione peroxidase 4 inhibitor (RSL3) in Huh7 and SK-HEP-1 cells...Necrostatin-1, ferrostatin-1, and deferoxamine repressed sulfasalazine-provoked membrane permeabilization, as detected by 7-aminoactinomycin D staining and lipid peroxidation measured using a C11-BODIPY probe. However, other RIPK1 inhibitors (necrostatin-1s and GSK2982772) and an IDO inhibitor (1-methyl-D-tryptophan) did not recover the decrease in cell viability induced by sulfasalazine. Necrostatin-1 potentiated sulfasalazine-induced expression of xCT, a catalytic subunit of system xc- in these cells. These results demonstrated that necrostatin-1 blocked ferroptosis through a mechanism independent from RIPK1 and IDO inhibition in Huh7 and SK-HEP-1 cells, indicating that its antioxidant activity should be considered when using necrostatin-1 as a RIPK1 inhibitor."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CDK7 • GPX4 • RIPK1

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis. (PubMed, BMJ Open Gastroenterol) - P2 | "GSK2982772 was generally well tolerated, with no treatment-related safety concerns identified. However, no significant differences in efficacy were observed between treatment groups, suggesting that GSK2982772 as monotherapy is not a promising treatment for patients with active UC."

Clinical • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Pain • Ulcerative Colitis • RIPK1

A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - P1/2; N=21; Active, not recruiting; Sponsor: GlaxoSmithKline; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Dermatology • Immunology • Psoriasis

Development of a Prototype, Once-Daily, Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772. (PubMed, Pharm Res) - P1 | "MT-12 h and MM-12 h provided a QD pharmacokinetic profile in the fasted state, however when MT-12 h was dosed with a high-fat meal a QD profile was not maintained. ( ClinicalTrials.gov Identifier: NCT03266172)."

Journal • RIPK1

A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - P1/2; N=21; Recruiting; Sponsor: GlaxoSmithKline; Phase classification: P1 ➔ P1/2

Clinical • Phase classification • Dermatology • Immunology • Psoriasis

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis. (PubMed, Arthritis Res Ther) - P2 | "These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA."

Clinical • Journal • Alopecia • Cardiovascular • Hematological Disorders • Immunology • Inflammation • Inflammatory Arthritis • Retinal Vein Occlusion • Rheumatoid Arthritis • Rheumatology • Thrombosis • Venous Thromboembolism • CRP • RIPK1

A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - P1; N=21; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Jul 2021 ➔ Oct 2021; Trial primary completion date: Jun 2021 ➔ Sep 2021

Clinical • Trial completion date • Trial primary completion date • Dermatology • Immunology • Psoriasis

Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov ."

Clinical • Journal • PK/PD data • Inflammation

A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - P1; N=21; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Dermatology • Immunology • Psoriasis

RIPK1 inhibitor ameliorates colitis by directly maintaining intestinal barrier homeostasis and regulating following IECs-Immuno crosstalk. (PubMed, Biochem Pharmacol) - "As a candidate in clinical study, GSK2982772 is the most well-developed drug of RIPK1 inhibitors, and we chose it as our study object...Taken together, RIPK1 inhibitor exerts suppressive function in intestinal inflammatory response possibly via protecting the intestinal epithelial barrier and maintaining the homeostasis of immune microenvironments. Eventually, the positive feedback immune response which triggered progressive epithelial cells injury could be restrained."

Journal • Gastrointestinal Disorder • Immunology