GSK2879552 / GSK - LARVOL DELTA

Histone demethylase LSD1 promotes castration-resistant prostate cancer by causing widespread gene expression derangements. (PubMed, IUBMB Life) - "In both orthotopic and metastatic tumor models, as well as in vitro cell cultures, the LSD1 inhibitor GSK2879552 demonstrated potent efficacy in suppressing PCa progression. To sum up, this study not only uncovers the oncogenic role of LSD1 in PCa but also validates the therapeutic promise of GSK2879552, furnishing novel perspectives and prospective targets for the clinical management of PCa."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FOXA1 • KDM1A • MMP13 • NKX3-1

The Histone Methyltransferase DOT1L Cooperates with LSD1 to Control Cell Division in Blast-Phase MPN (ASH 2024) - "To validate the synthetic lethal interaction between DOT1L and LSD1 we treated DOT1L-ko cells with Bomedemstat or GSK2879552 and discovered a 100-fold increase in drug sensitivity compared to WT cells (MTS-assay)...Consistent with this observation, treatment of the MPN blast-phase cell lines HEL or SET2 with LSD1-inhibitors in combination with the DOT1L-inhibitor EPZ5676 only showed a modest cooperative effect...This cooperation is caused by orchestrated binding of DOT1L and LSD1 at selected enhancer regions and is independent of DOT1L's enzymatic activity. This non-canonical function of DOT1L in blast-phase MPN provides a strong rationale for the development of targeted protein degraders (PROTACs) of DOT1L to exploit these findings therapeutically."

Epigenetic controller • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ANXA5 • CDK4 • CDK6 • DOT1L • DUSP6 • JAK1 • JAK2 • KMT2A • YBX1

Synthesis and biological evaluation of novel tranylcypromine-caffeic acid analogs as a potent inhibitor of LSD1 related osteoclast differentiation (ACS-Fall 2024) - "Therefore, new tranylcypromine (TCP) analogs was designed from the scaffold of GSK2879552, which is one of the moderate LSD1 inhibitors. In the co-crystal structure, it was confirmed that compound 6 binds to the LSD1/CoREST complex through FAD to reduce LSD1 demethylation enzyme activity. Ultimately, TCP-MP-CA (6) was discovered as a novel inhibitor of osteoclastogenesis."

The molecular background determines LSD1 inhibition sensitization of AML cells to gilteritinib and other kinase inhibitors (EACR 2024) - "Here, we hypothesise that the molecular background of AML determines the precise combinations of epigenetic and kinase targeting drugs that more effectively disrupt the dependencies that drive AML.Material and Methods Mega-erythroid (HEL, KMOE2 and CMK) and monocytic (MV4-11, P31 and NOMO1) AML cells were treated with the LSD1 inhibitor (LSD1i) GSK-2879552 for five days, followed by treatments with inhibitors of FLT3 (midostaurin and gilteritinib), MEK (trametinib), and PI3K (alpelisib, TGX-221, duvelisib, idelalisib and pictilisib aimed for α, β, δ/ɣ, δ and all isoforms) for three days. LSD1i reduced histone H3K79 methylation only in P31 cells and inhibitors of DOT1L, the enzyme that methylates H3K79, sensitized P31 cells to MEKi but not HEL cells to PI3Ki. These data suggest that the LSD1i induced sensitization to MEKi in P31 cells involves DOT1L, while the sensitization to PI3Kis in HEL cells may involve the lost of erythroid differentiation and energy metabolism..."

Acute Myelogenous Leukemia • DOT1L • FLT3 • PIK3CD

Id2 epigenetically controls CD8 T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex. (PubMed, Cell Mol Immunol) - "An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6Tim-3 Tex cells in tumors and the expression level of Tcf1 in Id2-deleted CD8 T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8 T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion."

IO biomarker • Journal • Oncology • CD8 • HAVCR2 • SLAMF6 • TCF3

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy. (PubMed, J Med Chem) - "Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577)...LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents."

Combination therapy • Journal • Review • Oncology

Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons. (PubMed, Nat Biotechnol) - "A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages."

Journal • CNS Disorders

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics. (PubMed, ACS Chem Biol) - "The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat)...For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors."

Journal • Review • Oncology • SNAI1

Recent advances of LSD1/KDM1A inhibitors for disease therapy. (PubMed, Bioorg Chem) - "Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology

Crucial Role of Lysine-Specific Histone Demethylase 1 in RANKL-Mediated Osteoclast Differentiation. (PubMed, Int J Mol Sci) - "This study identified GSK2879552, a lysine-specific histone demethylase 1 (LSD1) inhibitor, as a candidate for the treatment of osteoporosis from epigenetic modulator inhibitors...LSD1 can be employed as a positive regulator to promote osteoclast formation. Hence, inhibition of LSD1 activities is a potential target for preventing bone diseases characterized by excessive osteoclast activities."

Epigenetic controller • Journal • Orthopedics • Osteoporosis • Rheumatology • CTSK • KDM1A • NFATC1 • TNFSF11

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. (PubMed, Front Pharmacol) - "Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents."

Journal • Review • Acute Myelogenous Leukemia • Alzheimer's Disease • CNS Disorders • Esophageal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Mood Disorders • Oncology • Personality Disorder • Solid Tumor

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. (PubMed, Cancers (Basel)) - "We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated."

Journal • Acute Myelogenous Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Oncology • CD86 • CDKN1A • ITGAM • LRP1

JAK/BCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL. (PubMed, Leukemia) - "Using our ZEB2 ETP-ALL mouse model we previously documented the potential utility of the catalytic LSD1 inhibitor (GSK2879552) for treating mouse/human ETP-ALL...Treatment with LSD1i (particularly with the steric inhibitor SP2509) restored the expression of ZEB2/LSD1 pro-apoptotic BIM (BCL2L11) target. In combination with a JAK/STAT pathway inhibitor (JAKi, Ruxolitinib) or with a direct inhibitor of the anti-apoptotic BCL2 protein (BCL2i, ABT-199) resistance of human and mouse ETP-ALL to LSD1i was reversed. This new combination approach efficiently inhibited the growth of human and mouse ETP-ALL cells in vivo by enhancing their differentiation and triggering an apoptotic response. These results set the stage for novel combination therapies to be used in clinical trials to treat ETP-ALL patients."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L11 • ZEB2

Phase I trials of the lysine-specific demethylase 1 inhibitor, GSK2879552, as mono- and combination-therapy in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. (PubMed, Leuk Lymphoma) - No abstract available

Combination therapy • Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

C–H radioiodination of small molecule drugs (ACS-Sp 2022) - "We then performed the radioiodination of small molecule drugs under identical conditions; GSK923295, AZD9496, mivebresib, GSK2879552, sotorasib, tozasertib, KU-55933, and venetoclax. Radiochemical conversions of all small molecule drugs ranged from 70-90%, with the exception of sotorasib, which gave a lower yield of 40% and a mixture of ortho- para- substituents on the phenol moiety. In summary, we identified a new method for C–H radioiodination of small molecule drugs under mild conditions that enables access to new radiopharmaceuticals."

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. (PubMed, ACS Pharmacol Transl Sci) - "A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat)...Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds..."

Journal • Preclinical • Hematological Disorders • Oncology • Solid Tumor

BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes. (PubMed, Blood Adv) - "Moreover, treatment of AML cells with the HDAC inhibitor, pracinostat, and LSD1 inhibitor, GSK2879552, resulted in growth inhibition both in vitro and in vivo. High BCL11A expression is associated with worse prognosis in human AML patients. Blocking of BCL11A expression upregulates the expression of PU.1 target genes, and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FCGR3A

LSD1 as a Biomarker and the Outcome of Its Inhibitors in the Clinical Trial: The Therapy Opportunity in Tumor. (PubMed, J Oncol) - "However, for some of the inhibitors such as GSK2879552, though selective, potent, and effective, its disease control was poor as the rate of adverse events (AEs) was high in tumor patients causing clinical trial termination, and continuation could not be supported by the risk-benefit profile. Therefore, we propose that, to attain excellent clinical results of inhibitors of LSD1, much attention is required in designing appropriate dosing regimens, developing in-depth in vitro/in vivo mechanistic works of LSD1 inhibitors, and developing inhibitors of LSD1 that are reversible, safe, potent, and selective which may offer safer profiles."

Biomarker • Clinical • Journal • Review • Oncology

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=80; Recruiting; Sponsor: GlaxoSmithKline

Clinical • New P1 trial • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=80; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: GlaxoSmithKline; Trial primary completion date: Mar 2017 ➔ Sep 2018

Clinical • Trial primary completion date • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=24; Terminated; Sponsor: GlaxoSmithKline; N=100 ➔ 24; Recruiting ➔ Terminated; The risk benefit in relapsed refractory SCLC does not favor continuation of the study

Clinical • Enrollment change • Trial termination • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=24; Terminated; Sponsor: GlaxoSmithKline; Trial primary completion date: Sep 2018 ➔ Apr 2017

Clinical • Trial primary completion date • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=29; Terminated; Sponsor: GlaxoSmithKline; N=24 ➔ 29

Clinical • Enrollment change • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: GlaxoSmithKline; N=80 ➔ 100

Clinical • Enrollment change • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI