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Clinical, Journal: Inhibition of Receptor-Interacting Protein Kinase (Pubmed Central) - Feb 19, 2024 P1 The active enantiomer proved to be kinase selective. Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.
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Review, Journal: Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities. (Pubmed Central) - Nov 9, 2022 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.
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Journal: Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis. (Pubmed Central) - Feb 11, 2022 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.
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Journal, IO biomarker: Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma. (Pubmed Central) - Sep 29, 2021 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.
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Clinical, PK/PD data, Journal: Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects. (Pubmed Central) - Sep 25, 2021 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 .
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Clinical, Journal: Response to inhibition of receptor-interacting protein kinase 1 (RIPK1) in active plaque psoriasis: a randomized placebo-controlled study. (Pubmed Central) - May 25, 2021 The objective of this phase IIa multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis...Reductions in epidermal thickness and infiltration by CD3+ T cells in epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.
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Trial completion date, Trial initiation date, Trial primary completion date: A Study to Evaluate the Benefit and Safety of GSK2982772 in Moderate to Severe Psoriasis Participants (clinicaltrials.gov) - Apr 16, 2020 P1, N=21, Not yet recruiting, Eventually, the positive feedback immune response which triggered progressive epithelial cells injury could be restrained. Trial completion date: Feb 2021 --> Jul 2021 | Initiation date: May 2020 --> Sep 2020 | Trial primary completion date: Jan 2021 --> Jun 2021
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Journal: Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors; Analysis of Structure-Kinetic Relationships. (Pubmed Central) - Apr 19, 2019 ...On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux...Furthermore, oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). We also analyzed structure-kinetic relationship (SKR) for our novel chemical series and discussed the importance of evaluating drug-target residence time for lead optimization.
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Enrollment closed: GSK2982772 Study in Subjects With Ulcerative Colitis (clinicaltrials.gov) - Apr 16, 2019 P2, N=36, Active, not recruiting, We also analyzed structure-kinetic relationship (SKR) for our novel chemical series and discussed the importance of evaluating drug-target residence time for lead optimization. Recruiting --> Active, not recruiting
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Enrollment change, Trial completion date, Trial suspension, Trial primary completion date: A Safety and Pharmacokinetic (PK) Study of GSK2982772 in Healthy Subjects (clinicaltrials.gov) - Mar 23, 2018 P1, N=66, Suspended, Active, not recruiting --> Recruiting | Trial completion date: Jul 2018 --> Jan 2019 | Trial primary completion date: Jul 2018 --> Jan 2019 N=48 --> 66 | Trial completion date: May 2018 --> Oct 2018 | Recruiting --> Suspended | Trial primary completion date: May 2018 --> Oct 2018
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