GSK3145095 / GSK - LARVOL DELTA

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

A Phase I/II study of GSK3145095 alone and in combination with anticancer agents including pembrolizumab in adults with selected solid tumors. (ASCO 2019) - P1/2; "Part 3 represents a cohort expansion of Part 2. Part 4 may investigate the combination of additional anticancer agent(s) with one or more doses of GSK3145095 identified as safe in Part 1."

Clinical • Combination therapy • IO Biomarker • P1/2 data • PD(L)-1 Biomarker

First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P2; N=8; Terminated; Sponsor: GlaxoSmithKline; N=30 ➔ 8; Trial completion date: Nov 2022 ➔ Aug 2019; Recruiting ➔ Terminated; Trial primary completion date: Nov 2022 ➔ Aug 2019; The study was terminated following an internal review of the company's current research and development portfolio.

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination

Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer. (PubMed, ACS Med Chem Lett) - "Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors."

Clinical • Journal

First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: GlaxoSmithKline; Phase classification: P1/2 ➔ P2

Clinical • Combination therapy • Phase classification

First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors (clinicaltrials.gov) - P1/2; N=30; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting; Phase classification: P2 ➔ P1/2; N=220 ➔ 30

Clinical • Combination therapy • Enrollment change • Enrollment open • Phase classification