GSK2256098 / GSK - LARVOL DELTA

Design, synthesis and anti-glioblastoma multiforme activity of N-methoxy-2-(pyrimidin-4-ylamino)benzamide derivatives as focal adhesion kinase inhibitors. (PubMed, Mol Divers) - "Through a structure-based molecular hybridization strategy that integrated key pharmacophores from TAE-226 and the clinical candidate GSK2256098, a novel series of N-methoxy-2-(pyrimidin-4-ylamino)benzamide derivatives were designed and synthesized. Molecular docking simulations suggested that 7h combined within the ATP pocket of FAK, facilitated by synergistic hydrophobic interactions and key hydrogen bonds with residues ILE-428 and CYS-502. Overall, as a preliminary proof-of-concept, compound 7h represents a novel and promising FAK inhibitor, demonstrating potential for overcoming current therapeutic limitations in GBM."

Journal • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

A071401: Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients with Progressive Meningiomas (clinicaltrials.gov) - P2 | N=124 | Recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Trial completion date: Oct 2024 ➔ Jan 2028 | Trial primary completion date: Oct 2024 ➔ Jan 2026

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • AKT1 • CCND1 • CCND2 • CCND3 • CCNE1 • CDK4 • CDK6 • CDKN2A • NF2 • PIK3CA • PTCH1 • PTEN • SMO

New indole-linked 1,2,4-triazole derivatives as dual FAK inhibitors and apoptosis inducers targeting survival and migration in triple-negative breast cancer in-vitro. (PubMed, Sci Rep) - "Importantly, 4c efficiently suppressed FAK protein expression (61.3%) in TNBC, compared to the FAK inhibitor GSK-2256098 (70.7%). In vivo toxicity assessment confirmed good tolerability in mice without profound hepatic or renal impairments, while docking and ADMET analyses confirmed strong FAK binding affinity, and favourable pharmacokinetics of 4c. Collectively, 4c emerges as a promising FAK-targeted candidate for TNBC therapy."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Renal Disease • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CASP3

Identification and verification of ferroptosis-related core gene in postmenopausal osteoporosis based on bioinformatics analysis. (PubMed, PeerJ) - "Moreover, GSEA analysis indicated that PTEN is involved in functions and pathways associated with MAPK signaling, oxidative phosphorylation, mTOR signaling, etc. We discovered three drugs that bind tightly to PTEN, including CX-5461, UMI-77, and GSK2256098. PTEN was preliminarily identified and verified as a key ferroptosis gene in postmenopausal osteoporosis through bioinformatics analysis, and the diagnostic model constructed based on PTEN was of high value. These findings may provide novel perspectives on the pathogenesis of PMOP at the transcriptome level and establish a theoretical foundation for further research."

Journal • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • PTEN

Targeting focal adhesion kinase (FAK) in non-small cell lung cancer (NSCLC): Molecular mechanisms and combination therapeutic strategies. (PubMed, Biochem Pharmacol) - "Several FAK targeted inhibitors have advanced into clinical evaluation; for example, CEP-37440 is undergoing phase I trials, whereas GSK-2256098 has reached phase II trials. This review summarizes the structure and functional characteristics of FAK, its role in the pathogenesis of NSCLC, the research progress on FAK inhibitors, and the current status and prospects of combining FAK inhibitors with other therapies for NSCLC. The aim is to provide new insights for future clinical trial design and combination therapy strategies for NSCLC."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

A071401: Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas (clinicaltrials.gov) - P2 | N=124 | Recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Trial primary completion date: Jan 2026 ➔ Jan 2027

Trial primary completion date • Brain Cancer • Meningioma • Oncology • Solid Tumor • AKT1 • CCND1 • CCND2 • CCND3 • CCNE1 • CDK4 • CDK6 • CDKN2A • NF2 • PIK3CA • PTCH1 • PTEN • SMO

Targeting Focal Adhesion Kinase in Lung Diseases: Current Progress and Future Directions. (PubMed, Biomolecules) - "Some have progressed to clinical trials (Defactinib (Phase II), PF-562271 (Phase I), CEP-37440 (Phase I), PND-1186 (Phase I), GSK-2256098 (Phase II), BI-853520 (Phase I)), offering potential therapeutic targets for lung diseases. Emerging methodologies, such as PROTAC degraders and combination regimens, demonstrate significant potential for future research. Based on a comprehensive analysis of the relevant literature from 2015 to the present, this review briefly introduces the structure and function of FAK and discusses recent research advancements regarding FAK and its inhibitors in the context of pulmonary diseases."

Journal • Review • Acute Lung Injury • Asthma • Colorectal Cancer • Gastric Cancer • Immunology • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation

Sensitivity of Pancreatic Cancer Cell Lines to Clinically Approved FAK Inhibitors: Enhanced Cytotoxicity Through Combination with Oncolytic Coxsackievirus B3. (PubMed, Int J Mol Sci) - "In this study, we investigated the cytotoxicity of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines. Considering both oncolytic efficacy and the CI, the greatest enhancement in oncolytic activity was achieved when VS-4718 or CEP-37440 was combined with PD-H. These findings indicate that co-treatment with PD-H can potentiate the therapeutic activity of the selected FAKi and may represent a novel strategy to improve treatment outcomes in PDAC."

Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors. (PubMed, Clin Exp Med) - "Highly fluorescent tumor core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), while their proliferation ceased post-treatment in vitro. In contrast, cells derived from non-fluorescent tumor margins exhibited higher potency for the ATP synthase inhibitor (Gboxin), but their proliferation persisted post-treatment. Our study demonstrates a correlation between the adhesive and migration properties of cells and their sensitivity to therapeutics in different regions of the tumor within individual patients and between patients with GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Technical Feasibility and Protocol Compliance in the Second Stroke Pre-Clinical Assessment Network (ISC 2025) - "The Interventions, also selected through an NIH peer review process, included NanO2 (NuvOx) an oxygen delivery emulsion, tatCN19o (Neurexis) a CaM-kinase II inhibitor, GSK2256098 (GlaxoSmithKline/ETSU) a focal adhesion kinase inhibitor, GSK2256294 (GlaxoSmithKline/OHSU) a soluble epoxide hydrolase inhibitor, and BPN-27332 (Loxagen/MGH) a lipoxygenase inhibitor. The feasibility and protocol compliance seen in SPAN 1 have been replicated in stage 1 of the second trial, SPAN 2.1. Mortality resembles previous experience, with an improved survival in aged mice. SPAN 2 has advanced to Stage 2 where improved dose timing is implemented."

Compliance • Preclinical • Cardiovascular • Obesity

Modeling of FAK-PROTAC candidates from GSK2256098 analogs for targeted protein degradation. (PubMed, Biochem Biophys Res Commun) - "The stability of the complexes was analyzed using MDS and binding free energies were used to predict the binding affinity. Finally, based on desirable intermolecular interactions with the target and E3 ligase ProTAC4 was selected as the best candidate when compared with known FAK PROTAC GSK215."

Journal • Oncology • Targeted Protein Degradation

CONCEALMENT, BLINDING AND RANDOMIZATION IN A MULTI-CENTER, PRECLINICAL STROKE STUDY—THE SECOND STROKE PRECLINICAL ASSESSMENT NETWORK (ESOC 2024) - "Interventions selected are NanO2 (NuvOx) an oxygen delivery emulsion, tatCN19o (Neurexis) a CaM-kinase II inhibitor, GSK2256098 (GlaxoSmithKline/ETSU) a focal adhesion kinase inhibitor, GSK2256294 (GlaxoSmithKline/OHSU) a soluble epoxide hydrolase inhibitor, and BPN-27332 (Loxagen/MGH) a lipoxygenase inhibitor. Blinding in a multi-arm, multi-center preclinical trial is complex. Despite dissimilar compounds with differing solubilities and administration schedules, SPAN CC has designed a masked schedule that accommodates very different drugs and dosing schedules into a simplified, 2-tier trial using intravenous and intraperitoneal administration."

Preclinical • Cardiovascular

Roles and inhibitors of FAK in cancer: current advances and future directions. (PubMed, Front Pharmacol) - "To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies."

Journal • Review • Oncology

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma. (PubMed, J Gastrointest Oncol) - "One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC."

Journal • Metastases • P2 data • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9 • KRAS

A Study of GSK2256098 and Trametinib in Advanced Pancreatic Cancer (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: University Health Network, Toronto | Active, not recruiting ➔ Completed

Pan tumor • Trial completion • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations. (PubMed, J Clin Oncol) - "GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population."

Journal • P2 data • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • NF2

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations (J Clin Oncol) - P2 | N=124 | NCT02523014 | "Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events....GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls."

P2 data • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor

CPNE8 Promotes Gastric Cancer Metastasis by Modulating Focal Adhesion Pathway and Tumor Microenvironment. (PubMed, Int J Biol Sci) - "Our study demonstrated that CPNE8 promotes tumor progression via regulation of focal adhesion, and these effects can be rescued by focal adhesion kinase (FAK) inhibitor GSK2256098 or knockdown of FAK. In addition, CPNE8 was correlated significantly with the infiltration of cancer-associated fibroblasts and immune cells, as demonstrated by various algorithms, and high CPNE8 expression predicted poor efficacy of immune checkpoint therapy. Our findings suggest that CPNE8 modulates focal adhesion and tumor microenvironment to promote GC progression and invasiveness and could serve as a novel prognostic biomarker in GC."

Biomarker • Journal • Tumor microenvironment • Gastric Cancer • Gastrointestinal Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor

A Study of GSK2256098 and Trametinib in Advanced Pancreatic Cancer (clinicaltrials.gov) - P2 | N=16 | Active, not recruiting | Sponsor: University Health Network, Toronto | Trial completion date: Sep 2021 ➔ Jan 2023

Pan tumor • Trial completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

[VIRTUAL] Alliance A071401: Phase II trial of FAK inhibition in meningiomas with somatic NF2 mutations. (ASCO 2020) - P2 | "GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population."

P2 data • Brain Cancer • Dyslipidemia • Hepatology • Hypertriglyceridemia • Immunology • Meningioma • Oncology • Pain • Renal Disease • Solid Tumor

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (MOBILITY-002 Trial, NCT02428270). (ASCO-GI 2018) - P2; "GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC. Correlative studies are ongoing to evaluate RNA-expression subtypes and dynamic markers of pathway inhibition from serial tumor biopsies and cell free DNA."

Clinical • P2 data • Pancreatic Cancer

Vismodegib, FAK Inhibitor GSK2256098, Capivasertib, and Abemaciclib in Treating Patients With Progressive Meningiomas (clinicaltrials.gov) - P2; N=124; Recruiting; Sponsor: Alliance for Clinical Trials in Oncology; Suspended ➔ Recruiting; N=69 ➔ 124

Enrollment change • Enrollment open • Brain Cancer • Immunology • Meningioma • Oncology • Solid Tumor • AKT1 • CCND1 • CCND2 • CCND3 • CCNE1 • CDK4 • CDK6 • CDKN2A • MRI • PIK3CA • PTCH1 • PTEN • SMO

Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy. (PubMed, Molecules) - "Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. In addition, FAK degraders have been successfully developed through "proteolysis targeting chimera" (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents."

Journal • Review • Oncology • Targeted Protein Degradation

Vismodegib and FAK Inhibitor GSK2256098 in Treating Patients With Progressive Meningiomas (clinicaltrials.gov) - P2; N=69; Suspended; Sponsor: Alliance for Clinical Trials in Oncology; Trial primary completion date: Aug 2021 ➔ Oct 2024

Clinical • Trial primary completion date • Brain Cancer • Immunology • Meningioma • Oncology • Solid Tumor • PTCH1

Crispr/Cas-based modeling of NF2 loss in meningioma cells. (PubMed, J Neurosci Methods) - "Our model based on Crispr/Cas-based gene editing provides paired meningioma cells suitable to study functional consequences and therapeutic accessibility of NF2/merlin loss."

Journal • Brain Cancer • Fibrosis • Genetic Disorders • Meningioma • Neurofibromatosis • Oncology • Solid Tumor • NF2