GSK4524101 / Ideaya Biosci, GSK - LARVOL DELTA

A phase 1/2 dose escalation study of the oral DNA polymerase theta inhibitor (POLQi) GSK4524101 ± niraparib in adults with advanced or metastatic solid tumors. (ASCO 2025) - P1/2 | "Secondary endpoints include the PK of niraparib and the metabolite of GSK4524101 and incidence and duration of TEAEs and SAEs beyond the DLT observation period. The study is currently recruiting, with 17 patients having received doses across 9 sites in 2 countries as of January 10, 2025."

Clinical • Metastases • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Hypertension • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • HRD • POLQ

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Anticancer Activity of GSK4524101 Alone or With Niraparib in Participants With Solid Tumors (clinicaltrials.gov) - P1/2 | N=135 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Nov 2029 ➔ Jun 2027 | Trial primary completion date: Dec 2027 ➔ Jun 2027

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Identification of Novel Selective Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists. (PubMed, Curr Pharm Des) - "Our study provides new insight into the role of TRPV4 in pain and itch sensation and introduces LM0038, the most potent agonist, as a novel alternative to GSK101. With enhanced biological activity, it may serve as a valuable tool for studying TRPV4 function."

Journal • Pain

TRPV4 inhibition suppresses myocardial ischemic-reperfusion arrhythmia of mice by alleviating calcium handling abnormalities. (PubMed, Heart Rhythm) - "TRPV4 inhibition exerts antiarrhythmic effects post-IR by modulating CaMKII-dependent Ca2+ handling abnormalities, reducing CaT alternans and Ca2+ leak, without affecting APD."

Journal • Preclinical • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • Ventricular Tachycardia

IDEAYA Biosciences Announces Clearance of IND Application for Pol Theta Helicase Development Candidate GSK101 (IDE705) (PRNewswire) - "IDEAYA Biosciences, Inc...announced the clearance of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for initiation of a GSK-sponsored Phase 1/2 clinical trial to evaluate GSK101 (IDE705), a small molecule inhibitor of Pol Theta Helicase, in combination with niraparib, the GSK small molecule inhibitor of poly-(ADP-ribose) polymerase (PARP), for the treatment of patients having tumors with BRCA or other homologous recombination (HR) mutations or homologous recombination deficiency (HRD)....GSK is targeting first-in-human studies for GSK101 in the fourth quarter of 2023."

IND • New P1/2 trial • Oncology • Solid Tumor

STUDY OF FATTY ACIDS PROMOTING LYMPHOVASCULAR SPACE INVASION IN ENDOMETRIAL CANCER THROUGH ITGB3-ICAM1-TRPV4 MEDIATING MECHANICAL CROSSTALK BETWEEN CANCER CELLS AND ENDOTHELIAL CELLS (IGCS 2024) - "Transendothelial migration of EC cells could be stimulated by GSK101, an activator of TRPV4, and this effect was not seen after knockdown of TRPV4 in endothelial cells... Dyslipidemia could promote the development of LVSI in mice. The transendotheial migration of EC cells was promoted by free fatty acids, which might be related to the upregulation of ITGB3. The expression of ITGB3 in EC cells was elevated to induce clustering of ICAM-1 to increase mechanical forces in endothelial plasma membrane, to activate the mechanosensitive cation channel TRPV4."

Endometrial Cancer • Oncology • Sarcoma • Solid Tumor • ICAM1 • ITGB3 • TYK2

Transient Receptor Potential Vanilloid 4 Activation Within the Oral Cancer Microenvironment (IASP 2024) - "For all concentrations above 10nM GSK101 the response of SCs to the agonist was at least 50% greater than DOK and HSC-3, which did not differ in response (p<0.01, 1-way ANOVA, n = 8 wells)... TRPV4 is expressed on SC and oral cancer cells found within the cancer microenvironment. The responses of SCs, DOK, and HSC-3 to the TRPV4 agonist were robust and dose dependent. The TRPV4 response on SC is greater than DOK and HSC-3."

Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • Squamous Cell Carcinoma • TRPV4

Exploring How TRPV4 Activity is Modulated in Schwann Cells (IASP 2024) - "TRPV4 is functionally expressed by human and mouse SC and TRPV4 activity in human SC is increased by cell swelling when going from a hypertonic environment to an isotonic one. Given that SC swelling, which deforms the cell membrane, sensitizes TRPV4 to its specific agonist GSK101, we plan to study how stiffness of the extracellular matrix can influence TRPV4 activity on SCs, since oral cancers exhibit increased tissue stiffness (3,4) which also causes deformation of the cell. We will explore whether modulation of extracellular matrix stiffness contributes to oral cancer pain through SC TRPV4."

Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • GAPDH • TRPV4

TRPV4 Activation in Schwann Cells Regulates Cathepsin S Activity: Role in Oral Cancer Pain (IASP 2024) - "The functional expression of TRPV4 on SCs was studied with whole-cell patch clamp and the selective TRPV4 agonist (GSK101) and TRPV4 antagonist (HC067)... TRPV4 is functionally expressed on SCs in nerve fibers that innervate the oral cancer in patients who report pain. TRPV4 activation on SCs increased the extracellular activity of CTSS. Our findings suggest a potential mechanism for oral cancer pain that depends on TRPV4 activation on SCs and CTSS extracellular activity."

Head and Neck Cancer • Oncology • Oral Cancer • Pain • Solid Tumor • Tongue Carcinoma • CTSS • TRPV4

Tuning the Response of Synthetic Mechanogenetic Gene Circuits using Mutations in TRPV4. (PubMed, Tissue Eng Part A) - "Gene circuit output was dependent on the degree of TRPV4 activation secondary to GSK101 concentration or strain magnitude during loading. V620I constructs secreted more IL-1Ra compared to T89I across all experimental conditions, indicating that two mutations that cause similar functional changes to TRPV4 can result in distinct circuit activation profiles that differ from wild-type cells. In summary, we successfully demonstrate proof-of-concept that point mutations in TRPV4 that alter channel function can be used to tune the therapeutic output of mechanogenetic gene circuits."

Journal • Gene Therapies • TRPV4

LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling. (PubMed, J Cell Mol Med) - "Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice...Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification."

Journal • Dermatology • Infectious Disease • Pruritus • TLR4

First-in-human, phase 1/2 study of GSK4524101, an oral DNApolymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors. (ASCO 2024) - P1/2 | "Final publication number: 9686. Reused with permission."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Cardiovascular • Gastrointestinal Cancer • Hematological Malignancies • Hepatology • Hypertension • Leukemia • Myelodysplastic Syndrome • Oncology • Pancreatic Cancer • Solid Tumor • POLQ

TRPV4 mediates IL-1-induced Ca2+ signaling, ERK activation and MMP expression. (PubMed, FASEB J) - "Pre-incubation of cells with IL-1 Receptor Antagonist blocked Ca2+ entry induced by IL-1 or the TRPV4 agonist GSK101...The functional linkage of TRPV4 with IL-1R1 expands its repertoire of innate immune signaling processes by mediating IL-1-driven Ca2+ responses that drive matrix remodeling in fibroblasts. Thus, inhibiting TRPV4 activity may provide a new pharmacological approach for blunting matrix degradation in inflammatory diseases."

Journal • Inflammation • IL1B • MMP1 • MMP13 • TRPV4

First-in-human, phase 1/2 study of GSK4524101, an oral DNA polymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors (AACR 2024) - P1/2 | "Patients enrolled in part 1 will receive GSK4524101 alone or GSK4524101 plus niraparib; patients enrolled in part 2 will be randomized to either GSK4524101 plus niraparib or niraparib alone. Part 1 of this study is expected to complete in 2025."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Pancreatic Cancer • Solid Tumor • POLQ

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Anticancer Activity of GSK4524101 Alone or With Niraparib in Participants With Solid Tumors (clinicaltrials.gov) - P1/2 | N=135 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Nov 2025 ➔ Nov 2029 | Trial primary completion date: Jun 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx. (PubMed, Pharmaceuticals (Basel)) - "We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM. In single myocytes, the TRPV4 agonist (GSK101) evoked an increase in [Ca2+]i, characterized by a slow onset and a plateau phase...We conclude that contraction of ASM cells after stimulation with His or CCh promotes TRPV4 activation, the subsequent influx of Ca2+ and Na+, and the opening of L-VDCCs. The entry of Ca2+ into ASM cells via TRPV4 and L-VDCCs contributes to optimal smooth muscle contraction."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Modulation of TRPV4-mediated TNF-α expression in Müller glia and subsequent RGC apoptosis by statins. (PubMed, Exp Eye Res) - "Cells were pretreated with simvastatin or lovastatin before GSK101...Herein, we showed that statins can modulate gliosis and TNF-α expression in Müller cells, protecting RGCs. These data further support the neuroprotective effect of statins, promoting them as a potential treatment for glaucoma."

Journal • Glaucoma • Oncology • Ophthalmology • TNFA • TRPV4

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Anticancer Activity of GSK4524101 Alone or With Niraparib in Participants With Solid Tumors (clinicaltrials.gov) - P1/2 | N=135 | Recruiting | Sponsor: GlaxoSmithKline | Phase classification: P1 ➔ P1/2

Phase classification • Oncology • Solid Tumor

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Anticancer Activity of GSK4524101 Alone or With Niraparib in Participants With Solid Tumors (clinicaltrials.gov) - P1 | N=112 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting | Phase classification: P1/2 ➔ P1

Enrollment open • Phase classification • Oncology • Solid Tumor

IDEAYA Biosciences, Inc. Reports Third Quarter 2023 Financial Results and Provides Business Update (PRNewswire) - The IDEAYA Investor R&D Day will include participation from GSK and a key opinion leader that will showcase scientific insights and clinical development opportunities across IDEAYA's synthetic lethality pipeline, including IDE397 (MAT2A) in Phase 2, IDE161 (PARG) in Phase 1, GSK101/IDE705 (Pol Theta Helicase) in Phase 1, and the Werner Helicase program for which an IND submission is planned for 2024. In addition, IDEAYA will highlight its next generation initiatives in MTAP-deletion, including a wholly-owned program where a development candidate nomination is targeted in 2024, further advancing IDEAYA's multi-pronged strategy."

Clinical • IND • Oncology

Myoendothelial feedback in mouse mesenteric resistance arteries is similar between the sexes, dependent on nitric oxide synthase, and independent of TPRV4. (PubMed, Am J Physiol Heart Circ Physiol) - "Activation of TRPV4 with GSK101 (0.1-10 µM) induced similar dilation between the sexes...Similar expression of eNOS was found between the sexes with western blot. Thus, MEF is prominent and similar in murine 1 and 2 order mesenteric resistance arteries of both sexes, and reliant primarily on NOS, and secondarily on hyperpolarization, but not TRPV4."

Journal • Preclinical • NOS3

A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Anticancer Activity of GSK4524101 Alone or With Niraparib in Participants With Solid Tumors (clinicaltrials.gov) - P1/2 | N=112 | Not yet recruiting | Sponsor: GlaxoSmithKline

New P1/2 trial • Oncology • Solid Tumor

PIEZO1 is downregulated in glenohumeral chondrocytes in early cuff tear arthropathy following a massive rotator cuff tear in a mouse model. (PubMed, Front Bioeng Biotechnol) - " In native humeral head chondrocytes, chemical activation of PIEZO1 (Yoda1) significantly increased chondrocyte mechanical susceptibility against impact loads, while TRPV4 activation (GSK101) significantly decreased impact-induced chondrocyte death... In contrast to the hypothesis, PIEZO1 expression and activity is not increased, but rather downregulated, after massive RCT at the early stage of cuff tear arthropathy. These results may be secondary to the decreased axial loading after glenohumeral joint decoupling in RCT limbs."

Journal • Preclinical • Inflammation • Rheumatology

IDEAYA Biosciences, Inc. Reports First Quarter 2023 Financial Results and Provides Business Update (PRNewswire) - "Targeting a GSK-sponsored IND submission in Q2 2023 to evaluate Pol Theta Helicase inhibitor DC combination with niraparib for patients having tumors with HRD....Targeting selection of a Werner Helicase development candidate in 2023, in collaboration with GSK, with potential for $3 million milestone in connection with IND-enabling studies..."

IND • Pipeline update • Oncology • Solid Tumor

IDEAYA Biosciences, Inc. Reports 2022 Financial Results and Provides Business Update (PRNewswire) - "Targeting an IND submission, in collaboration with GSK, in the second quarter of 2023 to evaluate Pol Theta Helicase inhibitor DC combination with niraparib for patients having tumors with HRD...Targeting selection of a Werner Helicase development candidate in 2023, in collaboration with GSK, with potential for $3 million milestone in connection with IND-enabling studies..."

IND • Oncology • Solid Tumor