GSK2256098 / GSK - LARVOL DELTA

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

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

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

Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton. (PubMed, Bioorg Med Chem Lett) - "Compound 3d possessed significant FAK inhibitory activity with IC value of 18.10 nM better than the reference GSK-2256098 (IC = 22.14 nM)...This effect led to apoptosis induction and cell cycle arrest. Taken together, these results indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers."

Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • STAT3

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: Dec 2019 ➔ Sep 2021

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

Design, Synthesis and Biological Evaluation of Ring-fused Pyrazoloamino Pyridine/Pyrimidine Derivatives as Potential FAK Inhibitors. (PubMed, Bioorg Med Chem Lett) - "Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC < 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 μM in comparison with GSK2256098 as a reference. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain."

Journal • Oncology

[VIRTUAL] Focal adhesion kinase (FAK) inhibition overcomes cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) (AACR-II 2020) - "Cells were treated with the following commercially available FAK small molecule inhibitors: NVP-TAE-226 (Novartis); PF-573228, PF-562271, PF-431396 (Pfizer); GSK2256098 (GlaxoSmithKline); VS-6063 (Verastem). Our data suggests that FAK expression is associated with higher cancer stage. Its inhibition might have a role in overcoming cisplatin resistance and in affecting immunosuppressive signals in HNSCC. Immunocompetent syngeneic HNSCC animal models are currently ongoing."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • COL1A1 • Collagen Type IV • CXCL1 • CXCL8 • ITGA6 • LAMC2

[VIRTUAL] SJP1602, a selective and dual inhibitor of FAK and Pyk2 for treatment of triple negative breast cancer (AACR-II 2020) - "With increasing evidence of FAK as a promising therapeutic target in cancer, several small molecule inhibitors targeting FAK are currently on development and among them are defactinib (VS-6063) and GSK2256098, which are currently undergoing clinical investigation in combinatorial approach in solid tumors.In this study, we represent a novel small molecule inhibitor, SJP1602, targeting FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2). Furthermore, therapeutic index estimated by comparison of AUC at toxic and effective doses was higher than 10, rendering its potential clinical safety and efficacy.Taken together, these findings suggest SJP1602 as a small molecule inhibitor targeting FAK and Pyk2 with its outstanding selectivity and anti-tumor efficacy. Therefore, SJP1602 could be a promising therapeutic agent for TNBC patients that are resistant to conventional therapy as well as for cancer patients with drug resistance involving FAK activation."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD44 • HER-2