ganfeborole (GSK3036656) / GSK - LARVOL DELTA

Selectivity of the Time-Dependent M. tuberculosis LeuRS Inhibitor Ganfeborole Is Driven by Target Vulnerability. (PubMed, ACS Chem Biol) - "Additionally, mutations that reduce the affinity and residence time of ganfeborole-AMP on ecLeuRS result in antibacterial activity. We propose that the activity of ganfeborole toward M. tuberculosis is because mtLeuRS is a highly vulnerable target so that only low levels of enzyme need to be inhibited by the ganfeborole-tRNALeu complex in contrast to ecLeuRS, which we previously demonstrated is a low vulnerability target."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

PanACEA - STEP2C -01 (clinicaltrials.gov) - P2 | N=390 | Recruiting | Sponsor: Michael Hoelscher | N=270 ➔ 390 | Trial completion date: Feb 2025 ➔ Dec 2027 | Trial primary completion date: Feb 2025 ➔ Oct 2027

Enrollment change • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Early Bactericidal Activity, Safety & Tolerability of Oral GSK3036656 in a Dual Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin Susceptible Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=127 | Completed | Sponsor: GlaxoSmithKline | Recruiting ➔ Completed | Trial completion date: Nov 2024 ➔ May 2025 | Trial primary completion date: Nov 2024 ➔ May 2025 | Recruiting ➔ Completed

Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Nanofibrous supramolecular peptide hydrogels for controlled release of small-molecule drugs and biologics. (PubMed, Nat Nanotechnol) - "Pharmacokinetic studies reveal that SABER hydrogels extend the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth compared with oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for 6 days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Drug-target residence time and the post-antibiotic effect: Strategies to improve dosing regimens (ACS-Fall 2025) - "This includes ganfeborole and epetraborole which are benzoxaborole inhibitors of leucyl-tRNA synthetase (LeuRS), and inhibitors of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). We have studied the residence time and PAE of these compounds and have determined that decreasing the resynthesis rate of LeuRS synthesis leads to an increase in PAE. We have also developed a high-throughput assay to screen the Escherichia coli Keio collection of ∼4000 deletion strains to identify genes that enhance the PAE caused by antibacterial compounds and have identified a molecular link between LpxC stability and synthesis of the LPS core antigen."

Infectious Disease

Ganfeborole in combination with novel antitubercular agent BTZ-043 administered for 14-days to participants with rifampicin-susceptible pulmonary tuberculosis: interim analysis results (ESCMID Global 2025) - No abstract available

Combination therapy • Infectious Disease • Respiratory Diseases • Tuberculosis

Characterising Mycobacterium tuberculosis resistance mechanisms to ganfeborole and monitoring drug resistance during Phase 2a clinical trial (ESCMID Global 2025) - No abstract available

Clinical • P2a data • Infectious Disease • Respiratory Diseases • Tuberculosis

Annual progress of new drugs and new regimens for anti-tuberculosis treatment (2024) (PubMed, Zhonghua Jie He He Hu Xi Za Zhi) - "There are multiple new drugs in the clinical trial stage, such as macozinone, sutezoid, alpiberctin, and GSK3036656. The effectiveness, safety, and resistance issues of marketed drugs such as linezolid, bedaquiline, and delamanid are also of great concern...WHO has also updated the preventive treatment plan for people at high risk of TB. This article reviews the literature published from October 1, 2023 to September 30, 2024."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A Study to Investigate the Pharmacokinetics of a Combined Oral Contraceptive When Given Alone and in Combination With GSK3036656 in Female Participants of Non-childbearing Potential Aged 18 to 65 Years of Age (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: GlaxoSmithKline | Recruiting ➔ Completed | Trial completion date: Oct 2024 ➔ Jul 2024 | Trial primary completion date: Oct 2024 ➔ Jul 2024

Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A Study to Investigate the Pharmacokinetics of a Combined Oral Contraceptive When Given Alone and in Combination With GSK3036656 in Female Participants of Non-childbearing Potential Aged 18 to 65 Years of Age (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice. (PubMed, Nat Commun) - "Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity."

Journal • Preclinical • Cardiovascular • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • TRIM29

Luteolin, apigenin, and chrysin inhibit lipotoxicity-induced NLRP3 inflammasome activation and autophagy damage in macrophages by suppressing endoplasmic reticulum stress. (PubMed, Environ Toxicol) - "In the presence of the PERK inhibitor GSK2656157, PA-induced CHOP and TXNIP expression and caspase-1 activation were mitigated. Compared with PA treatment alone, Bcl-2 coupled to beclin-1 was elevated and autophagy was reversed by the JNK inhibitor SP600125...Moreover, TXNIP binding to NLRP3 and IL-1β release in response to LPS/PA challenge were reduced. These results suggest that luteolin, apigenin, and chrysin protect hepatic macrophages against PA-induced NLRP3 inflammasome activation and autophagy damage by attenuating endoplasmic reticulum stress."

IO biomarker • Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • BCL2 • BECN1 • IL1B • MAPK8 • NLRP3 • TXNIP

A Study to Investigate the Pharmacokinetics of a Combined Oral Contraceptive When Given Alone and in Combination With GSK3036656 in Female Participants of Non-childbearing Potential Aged 18 to 65 Years of Age (clinicaltrials.gov) - P1 | N=25 | Not yet recruiting | Sponsor: GlaxoSmithKline

Combination therapy • New P1 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Insufficient secretion of pancreatic FGF21 is the toxicological mechanism and therapeutic target of asparaginase-associated pancreatitis. (PubMed, Toxicol Appl Pharmacol) - "Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pancreatitis • ATF3 • ATF4 • FGF21

Invited Talk: Controlling Drug Release from Self-Assembled Peptide Hydrogels using Dynamic Covalent Bonding (ACS-Sp 2024) - "These functionalized hydrogels were then loaded with boronic acid-containing drugs, including (GSK656, bortezomib, tavaborole, and ixazomib), a modified small-molecule drug (1V209), two therapeutic antibodies (amivantamab and omodenbamab), and one antibody-drug conjugate (trastuzumab deruxtecan) and characterized in vitro and in vivo using mass spectrometry, circular dichroism, in vitro equilibration assays, in vivo mass spectrometry imaging, and pharmacokinetic studies in mice. Boronic acid-functionalized antibodies remained stable within the hydrogel and were released from the hydrogel depo over up to 8 weeks in vivo. These results indicate that SHA-functionalized hydrogels represent a robust and versatile platform for delivering a variety of drugs and may have the potential to enhance clinical drug efficacy through sustained and/or localized release."

Early Bactericidal Activity, Safety & Tolerability of Oral GSK3036656 in a Dual Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin Susceptible Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=128 | Recruiting | Sponsor: GlaxoSmithKline | N=70 ➔ 128

Enrollment change • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial. (PubMed, Nat Med) - P2a | "GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase...Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days...Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281 ."

Journal • P2a data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Targeting PERK-ATF4-P21 axis enhances the sensitivity of osteosarcoma HOS cells to Mppα-PDT. (PubMed, Aging (Albany NY)) - "In conclusion, we found that the combination of MPPα-PDT and GSK2656157 enhanced apoptosis in HOS cells by inhibiting autophagy. Mechanistically, this autophagy is p21-dependent and can be suppressed by GSK2656157, thereby enhancing sensitivity to MPPα-PDT."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ATF4

Juan-tong-yin potentially impacts endometriosis pathophysiology by enhancing autophagy of endometrial stromal cells via unfolded protein reaction-triggered endoplasmic reticulum stress. (PubMed, J Ethnopharmacol) - "JTY ameliorates EMs by activating PERK associated with unfolded protein reaction, enhancing cell ER stress and autophagy, improving the inflammatory microenvironment, and decreasing the migration and invasion of ESCs."

Journal • Stroma • Endometriosis • Gynecology • Infertility • Inflammation • Musculoskeletal Pain • Pain • Sexual Disorders • Women's Health • ATF4 • BECN1 • IL18 • NLRP3 • TCF4

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway. (PubMed, Cardiovasc Diabetol) - "These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • ATF4 • HSPA5 • VEGFB

PARADIGM4TB: Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (clinicaltrials.gov) - P2 | N=2500 | Recruiting | Sponsor: University College, London | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Sevoflurane postconditioning alleviates hypoxic-ischemic brain damage in rats by inhibiting the endoplasmic reticulum stress PERK/ATF4/CHOP pathway. (PubMed, Tissue Cell) - "Investigating the role of sevoflurane postconditioning (SPC) in HIBD, we conducted experiments involving HIBD modeling, SPC treatment, and interventions with the PERK inhibitor GSK2656157 or the PERK activator CCT020312, administered 30 min before modeling, followed by SPC treatment. However, pre-modeling treatment with the PERK activator CCT020312 counteracted the protective effects of SPC against HIBD in rats. In conclusion, SPC alleviates neuronal apoptosis in the hippocampus CA1 area of HIBD rats by inhibiting the endoplasmic reticulum stress pathway PERK/ATF4/CHOP, thereby mitigating HIBD in rats."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Vascular Neurology • ATF4 • BAX • BCL2 • HSPA5

Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord. (PubMed, Anesthesiology) - "Astrocyte ER stress sensors PERK and IRE1 facilitated morphine tolerance and hyperalgesia through upregulation of LCN2 and NLRP3 in the spinal cord."

Journal • Preclinical • Inflammation • Pain • ATF4 • ERN1 • LCN2 • NLRP3 • TCF4 • TXNIP

GSK2656157, a PERK Inhibitor, Alleviates Pyroptosis of Macrophages Induced by Mycobacterium Bacillus Calmette-Guerin Infection. (PubMed, Int J Mol Sci) - "Similarly, GSK2656157 treatment downregulated the expressions of pro-caspase-1, caspase-1 p20, caspase-11, IL-1β p17, IL-18 p22, GSDMD, GSDMD-N, and p-PERK, as well as reducing fibrous tissue hyperplasia, inflammatory infiltration, and the bacterial load in the lung tissue of C57BL/6J mice infected with BCG. In conclusion, the inhibition of PERK alleviated pyroptosis induced by BCG infection, which has an effect of resisting infection."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • IL18 • IL1B

PARADIGM4TB: Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (clinicaltrials.gov) - P2 | N=2500 | Not yet recruiting | Sponsor: University College, London | Phase classification: P2b ➔ P2

Phase classification • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis