Molecular Basket Trial In Multiple Malignancies With Common Target Pathway Aberrancies: A Phase II Trial of GSK2256098 and Trametinib in Patients With Advanced Pancreatic Cancer

This is a phase 2 study (the second phase in testing a new drug or combination to see how effect the drug or combination is) of investigational drugs GSK2256098 and Trametinib.
The purpose of the study is to evaluate the antitumor activity of GSK2256098 and Trametinib in patients with advanced pancreatic cancer.

Start Date01 Apr 2016

Sponsor / Collaborator

University Health Network

[+1]

NCT02551653

/ CompletedPhase 1

A Microdose Study to Evaluate the Biodistribution of [11C]-GSK2256098 in the Lungs and Heart of Healthy Subjects and Idiopathic Pulmonary Arterial Hypertension (PAH) Patients Using Positron Emission Tomography (PET)

Pulmonary arterial hypertension (PAH) involves the narrowing of blood vessels connected to and within the lungs. Focal adhesion kinase (FAK) is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes which leads to stiffening and thickening of blood vessels in lungs. This further increases the blood pressure within the lungs and impairs their blood flow. This study aims to demonstrate biodistribution of FAK inhibitor, GSK2256098, in cardiopulmonary sites i.e. heart and lung tissues. The uptake of 11C-radiolabelled GSK2256098 within the lung and / or heart of healthy subjects and idiopathic pulmonary arterial hypertension (iPAH) patients will be assessed using Positron Emission Tomography (PET). Based on study results the decision as to whether a follow-on phase 2 trial should be initiated to investigate the therapeutic utility of GSK2256098 in iPAH will be decided. Sufficient number of subjects will be screened (up to 30 days prior to scan) to enrol 12 healthy subjects and 12 PAH patients in the study. Enrolled subjects will receive a microdose of [11C]-GSK2256098 on a scanning day which will be followed by the follow-up visit (2-4 weeks post-last dose).

Start Date17 Nov 2015

Sponsor / Collaborator

GSK Plc

NCT02523014

/ RecruitingPhase 2IIT

Phase II Trial of SMO/ AKT/ NF2/CDK Inhibitors in Progressive Meningiomas With SMO/ AKT/ NF2/CDK Pathway Mutations

This phase II trial studies how well vismodegib, focal adhesion kinase (FAK) inhibitor GSK2256098, and capivasertib work in treating patients with meningioma that is growing, spreading, or getting worse (progressive). Vismodegib, FAK inhibitor GSK2256098, capivasertib, and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date28 Sep 2015

Sponsor / Collaborator

Alliance Foundation Trials LLC

[+4]

100 Clinical Results associated with GSK-2256098

100 Translational Medicine associated with GSK-2256098

100 Patents (Medical) associated with GSK-2256098

Literatures (Medical) associated with GSK-2256098

01 Dec 2024·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Modeling of FAK-PROTAC candidates from GSK2256098 analogs for targeted protein degradation

Article

Author: Lee, Keun Woo ; Parate, Shraddha ; Jung, Tae Sung ; Kumar, Vikas ; Ro, Hyeon-Su

Protein inhibition via the traditional drug-designing approach has been shown to be an effective method for developing numerous small-molecule-based therapeutics. In the last decade, small inhibitors-guided protein degradation has arisen as an alternative method with the potential to fulfill the drug requirement for undruggable targets. Focal adhesion kinase (FAK) is a crucial modulator of the growth and spread of tumors, apart from it also acts as a scaffold for signaling of other proteins. FAK inhibitors have thus far had unsatisfactory results in clinical trials for cancer applications. Unlike prior attempts to control FAK expression, which were restricted to kinase domain inhibition with limited success in clinical research, protein degradation has the potential to concurrently disrupt FAK's kinase and scaffolding function. Recently, several FAK degraders were reported based on FAK Type I inhibitors using complex chemical synthesis approaches. Interestingly, recently a ternary complex was published revealing the binding mode of the FAK-PROTAC-E3 complex. This complex opens an avenue for the development of rational PROTAC design against FAK protein. Therefore, in the present study, we selected the most active Type I FAK inhibitor GSK2256098. The binding mode of the inhibitor prompted us to identify the most suitable analog for PROTAC design. We have identified a high-affinity analog that is suitable for PTOTAC design through the application of molecular docking (MD) and molecular dynamics simulations (MDS). Further based on the ternary FAK-PROTAC-E3 complex we build a binary complex FAK-Hit-E3-VHL between both proteins. Using the structure-based approach ten different potential FAK PROTACs candidates were designed. 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.

01 Nov 2024·JOURNAL OF CELLULAR PHYSIOLOGY

Ankrd1 inhibits the FAK/Rho‐GTPase/F‐actin pathway by downregulating ITGA6 transcriptional to regulate myoblast functions

Article

Author: Hu, Jinling ; Lei, Minggang ; Lian, Weisi ; Huang, Cheng ; Kang, Tingting ; Zhong, Qiqi

Abstract:

Skeletal muscle constitutes the largest percentage of tissue in the animal body and plays a pivotal role in the development of normal life activities in the organism. However, the regulation mechanism of skeletal muscle growth and development remains largely unclear. This study investigated the effects of Ankrd1 on the proliferation and differentiation of C2C12 myoblasts. Here, we identified Ankrd1 as a potential regulator of muscle cell development, and found that Ankrd1 knockdown resulted in the proliferation ability decrease but the differentiation level increase of C2C12 cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyzes as well as RNA‐seq results showed that Ankrd1 knockdown activated focal adhesion kinase (FAK)/F‐actin signal pathway with most genes significantly enriched in this pathway upregulated. The integrin subunit Itga6 promoter activity is increased when Ankrd1 knockdown, as demonstrated by a dual‐luciferase reporter assay. This study revealed the molecular mechanism by which Ankrd1 knockdown enhanced FAK phosphorylation activity through the alteration of integrin subunit levels, thus activating FAK/Rho‐GTPase/F‐actin signal pathway, eventually promoting myoblast differentiation. Our data suggested that Ankrd1 might serve as a potential regulator of muscle cell development. Our findings provide new insights into skeletal muscle growth and development and valuable references for further study of human muscle‐related diseases.

01 Jan 2024·GUT

FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer

Article

Author: Biankin, Andrew V ; Kallor, Ashwin Adrian ; Serrels, Alan ; Canel, Marta ; Davidson, Catherine ; Lonergan, David W ; Upstill-Goddard, Rosie ; von Kriegsheim, Alex ; Byron, Adam ; Alfaro, Javier ; Sławińska, Aleksandra Dominika

Objective:

Immunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumour microenvironment contribute to this lack of response. Here, we aimed to further investigate the immunoregulatory function of focal adhesion kinase (FAK) in PDAC, with specific emphasis on regulation of the type-II interferon response that is critical in promoting T-cell tumour recognition and effective immunosurveillance.

Design:

We combined CRISPR, proteogenomics and transcriptomics with mechanistic experiments using a KrasG12Dp53R172Hmouse model of pancreatic cancer and validated findings using proteomic analysis of human patient-derived PDAC cell lines and analysis of publicly available human PDAC transcriptomics datasets.

Results:

Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells. Regulation of the immunoproteasome by FAK is a critical determinant of this response, optimising the physicochemical properties of the peptide repertoire for high affinity binding to MHC-I. Expression of these pathways can be further amplified in a STAT1-dependent manner via co-depletion of FAK and STAT3, resulting in extensive infiltration of tumour-reactive CD8 T-cells and further restraint of tumour growth. FAK-dependent regulation of antigen processing and presentation is conserved between mouse and human PDAC, but is lost in cells/tumours with an extreme squamous phenotype.

Conclusion:

Therapies aimed at FAK degradation may unlock additional therapeutic benefit for the treatment of PDAC through increasing antigen diversity and promoting antigen presentation.

News (Medical) associated with GSK-2256098

08 May 2023

·www.prnewswire.com

Global Pancreatic Cancer Competitive Landscape Report 2023: Comprehensive Insights about 250+ Companies and 300+ Drugs

DUBLIN, May 8, 2023 /PRNewswire/ -- The "Pancreatic Cancer - Competitive landscape, 2023" report has been added to ResearchAndMarkets.com's offering. This "Pancreatic Cancer- Competitive landscape, 2023" report provides comprehensive insights about 250+ companies and 300+ drugs in Pancreatic Cancer Competitive landscape. It covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space. In March 2023, Adaptimmune Therapeutics plc. and TCR Therapeutics Inc. (NASDAQ: TCRR), announced entry into a definitive agreement under which Adaptimmune will combine with TCR in an all-stock transaction to create a preeminent cell therapy company focused on treating solid tumors. The combination provides extensive benefits for clinical development and product delivery supported by complementary technology platforms. As a result, and following the closing of the transaction, it is anticipated that the combined company's cash runway will extend into 2026. In February 2023, Akamis Bio, announced an expansion of its ongoing partnership with the Parker Institute for Cancer Immunotherapy (PICI) to include a clinical collaboration with the Cancer Research Institute (CRI) that will focus on advancing novel treatments for pancreatic cancer. As part of the Akamis Bio, PICI, and CRI partnership, NG-350A, an immuno-stimulatory tumor gene therapy driving intratumoral expression of a CD40 agonist monoclonal antibody, will be evaluated in combination with standard-of-care chemotherapy and the CTLA-4 inhibitor ipilimumab (YERVOY). In February 2023, Gritstone bio, Inc. announced that it has entered into a clinical trial agreement with the National Cancer Institute (NCI), an institute of the National Institutes of Health, to evaluate an autologous T cell therapy expressing a T cell receptor targeting mutated KRAS in combination with Gritstone's KRAS-directed vaccine candidate, SLATE-KRAS, in a Phase 1 study. Under the terms of the agreement, NCI will identify patients with metastatic cancer that are eligible for adoptive cell transfer based on the presence of a G12V or G12D KRAS mutation (KRASmut). In February 2023, Keymed Biosciences Inc., jointly announced a global exclusive license agreement with AstraZeneca for CMG901, a potential first-in-class Claudin 18.2 antibody drug conjugate (ADC). Under the license agreement, AstraZeneca will be responsible for the research, development, manufacture and commercialization of CMG901 globally. CMG901 is currently in a Phase I clinical trial for the treatment of Claudin 18.2-positive solid tumors. In January 2023, AIM ImmunoTech Inc. announced it has entered into an external sponsored collaborative clinical research agreement with Erasmus MC and AstraZeneca. Under the agreement, Erasmus MC is planning to perform an investigator-initiated clinical study, entitled "Combining anti-PD-L1 immune checkpoint inhibitor durvalumab with TLR-3 agonist rintatolimod in patients with metastatic pancreatic ductal adenocarcinoma for therapy effect. DURIPANC Study," in which it will use both Study Drugs provided by AstraZeneca and AIM ImmunoTech. Pancreatic Cancer Analytical Perspective In-depth Commercial Assessment: Pancreatic Cancer Collaboration Analysis by Companies The Report provides in-depth commercial assessment of drugs that have been included, which comprises collaboration, agreement, licensing and acquisition - deals values trends. The sub-segmentation is described in the report which provide company-company collaboration (licensing/partnering), company academic collaboration and acquisition analysis in tabulated form. Key Questions Answered Current Treatment Scenario and Emerging Therapies: How many companies are developing Pancreatic Cancer drugs? How many Pancreatic Cancer drugs are developed by each company? How many emerging drugs are in mid-stage, and late-stage of development for the treatment of Pancreatic Cancer? What are the key collaborations (Industry-Industry, Industry-Academia), Mergers and acquisitions, licensing activities related to the Pancreatic Cancer therapeutics? What are the recent trends, drug types and novel technologies developed to overcome the limitation of existing therapies? What are the clinical studies going on for Pancreatic Cancer and their status? What are the key designations that have been granted to the emerging and approved drugs? Key Players Panbela Therapeutics ERYtech Pharma Jiangsu HengRui Medicine Co., Ltd. FibroGen Novartis AG AB Science TME Pharma AG Intensity Therapeutics Silenseed LTD SynerGene Therapeutics Elevation oncology Salspera LLC Redx Pharma Plc AIM ImmunoTech Inc. Rain Oncology Jazz Pharmaceuticals Invyte Corporation Immodulon Therapeutics Ltd GSK plc Merck Sharp & Dohme LLC Roche Helsinn Healthcare SA Argenus Inc. Actuate Therapeutics OSE Immunotherapeutics Incyte Corporation Galera Therapeutics CSPC ZhongQi Pharmaceutical Technology Astellas Pharma Global Development, Inc. NanOlogy Theriva Biologics AstraZeneca Berg, LLC Agenus ABVC BioPharma, Inc. Boehringer Ingelheim Alligator Bioscience CARsgenTherapeutics Co.,Ltd Purple Biotech Ltd. Lisata Therapeutics Chongqing Precision Biotech Co., Ltd Cybrexa Therapeutics Bold Therapeutics BioNTech SE Bristol-Myers Squibb DEKA Biosciences Senhwa Biosciences Cue Biopharma Carisma Therapeutics Inc Key Products Olaptesed pegol INT230-6 SBP-101 Masitinib NIS793 siG12D LODER SGT-53 Seribantumab Salmonella-IL2 RXC004 Rintatolimod RAIN-32 Lurbinectedin Retifanlimab IMM-101 GSK2256098 Belzutifan Atezolizumab Anamorelin AGEN1423 Elraglusib OSE2101 Epacadostat GC4711 Docetaxel Zolbetuximab NanoPac VCN-01 Danvatirsen BPM31510 Botensilimab ABV-1703 BI 907828 Mitazalimab CT041 CM24 CEND-1 CEA-targeted CAR-T cells CBX-12 BOLD-100 BNT141 BMS-813160 DK210 CX-5461 CUE-102 CT-0508 For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

ImmunotherapyLicense out/inVaccinePhase 1ADC

100 Deals associated with GSK-2256098

External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adenocarcinoma	Phase 2	Canada	GSK Plc	01 Apr 2016
Pancreatic Cancer	Phase 2	Canada	GSK Plc	01 Apr 2016
Meningioma	Phase 2	United States	GSK Plc	28 Sep 2015
Neurofibromatosis 2	Phase 2	United States	GSK Plc	28 Sep 2015
Idiopathic pulmonary arterial hypertension	Phase 1	United Kingdom	GSK Plc	17 Nov 2015
Advanced Malignant Solid Neoplasm	Phase 1	France	GSK Plc	18 Nov 2013
Advanced Malignant Solid Neoplasm	Phase 1	United Kingdom	GSK Plc	18 Nov 2013
Recurrent Glioblastoma	Phase 1	Australia	GSK Plc	27 Jul 2010
Recurrent Glioblastoma	Phase 1	France	GSK Plc	27 Jul 2010
Recurrent Glioblastoma	Phase 1	United Kingdom	GSK Plc	27 Jul 2010

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02523014 (Alliance A071401, ASCO2020) Manual	Phase 2	Meningioma NF2 Mutation	36	GSK-2256098 (Grade I meningiomas)	upawllwxqg(kfsnmqqaga) = kbsflnphtn lsetdfyvbq (wodisrfvox, 52 - 98)	Positive	25 May 2020
				GSK-2256098 (Grade II/III meningiomas)	upawllwxqg(kfsnmqqaga) = khitmtarjd lsetdfyvbq (wodisrfvox, 16 - 55)
NCT02551653 (CTgov)	Phase 1	Idiopathic pulmonary arterial hypertension	10	GSK2256098 (PAH Participants)	mzkmaqigak(vhwqhoskwv) = rutlobbgpa jdelojiedd (pdarisdnac, 0.14769) View more	-	17 Aug 2018
				GSK2256098 (Healthy Volunteers)	mzkmaqigak(vhwqhoskwv) = fzbckoonbv jdelojiedd (pdarisdnac, 0.18754) View more
NCT02428270 (ASCO_GI 12018 \| ASCO_GI 22018) Manual	Phase 2	Advanced Pancreatic Ductal Adenocarcinoma Second line	16	trametinib+GSK2256098	qluntsufel(okknfcnaeo) = fisixfwzam xlanbfjraw (awkwtiennk, 1.5 - 1.8) View more	Negative	19 Jan 2018
NCT01938443 (ASCO2015) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	24	GSK2256098+trametinib (total population)	njpdadrfpr(mmiqwtimiq) = zpqcusrnnb hrbuejgykl (meqeywfbzo )	Positive	20 May 2015
				GSK2256098+trametinib (mesothelioma pts)	pfzhnzwlrw(tjuqkjpnxc) = xvqltwuqzv fkwydmjmiu (nmbojzsvqp )
NCT01138033 (ASCO2012)	Phase 1	HR-positive/HER2-low Solid Tumors	57	GSK2256098	uogasfrvct(rbjzetbsvy) = kiwzuvaqpg vtldwnrfjj (uvexcpamim ) View more	-	20 May 2012

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