RG2833 / BioMarin, Repligen, Johns Hopkins University - LARVOL DELTA

Six promising drug repurposing candidates for Alzheimer's disease and their sex-specific mechanisms and efficacy. (PubMed, Neural Regen Res) - "These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease. This review underscores the need for a multifaceted approach to Alzheimer's disease treatment, combining symptom relief with disease modification."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation

Histone deacetylase inhibitor, Vorinostat, reverses EGFR-TKI resistance in lung adenocarcinoma via degradation of MET (AACR 2025) - "Next, to explore the mechanism(s) through which VS enhances MET-dependent cell death, we performed several experiments including 1) real-time RT-PCRs and western blots to discern if VS regulates the expression of MET at transcriptional or translational level; 2) cycloheximide chase assays to examine the impact of VS on MET protein stability; 3) treatment with RGFP109, a HDAC1/HDAC3 selective inhibitor, to specify which HDAC(s) may be involved in this process. Our study suggests that VS promotes cell death of LUAD cells with amplification of MET via inducing HDAC1/3-mediated MET protein degradation. In combination with Osimertinib, VS reverses the amplification of MET-induced TKI resistance in LUAD cells. This combination might be therapeutically exploitable to overcome acquired TKI resistance caused by MET amplification in NSCLC patients."

Epigenetic controller • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HDAC3 • MET

Brain-penetrant histone deacetylase inhibitor RG2833 improves spatial memory in females of an Alzheimer's disease rat model. (PubMed, J Alzheimers Dis) - "Our study highlights the potential of histone-modifying therapeutics such as RG2833 to improve cognitive behavior and drive the expression of immediate early, synaptic plasticity and memory consolidation genes, especially in female AD patients."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • EGR1 • FOS

Schlafen11 is a powerful biomarker of chemosensitivity in medulloblastomas (SNO 2023) - "Importantly, markedly increased sensitivity to cisplatin and SN-38 was seen in initially SLFN11-negative medulloblastoma cells also treated with RG2833, suggesting an approach by which more aggressive medulloblastoma subtypes might be targeted. Our findings suggest a novel mechanism for the increased chemosensitivity of some medulloblastoma subtypes linked to a specific biomarker, as well as a novel combinatorial chemotherapeutic strategy for the treatment of more aggressive medulloblastoma subtypes (Groups 3 and 4) lacking SLFN11."

Biomarker • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • SLFN • SLFN11

Sex-specific effects of the HDAC inhibitor RG2833 in mitigating spatial memory performance deficits in an Alzheimer's disease transgenic rat model. (Neuroscience 2023) - "These data indicate that histone modifying therapies can improve cognitive behavior by improving the expression of neuroprotective genes and by modulating the activation of immune cells and possibly dampening the inflammatory response. Based on our data, we propose that RG2833 could be an effective therapeutic that could benefit female patients with AD."

Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Mental Retardation • Psychiatry • EGR1 • FOS

HDAC INHIBITION INVOLVES CD26 EXPRESSION ON MULTIPLE MYELOMA CELLS VIA THE C-MYC/SP1-MEDIATED PROMOTER ACTIVATION AND OVERCOMES THERAPEUTIC RESISTANCE BY HUMANIZED ANTIBODY (EHA 2023) - "Although the cell surface expression of CD26 was relatively low or not detected on 5 myeloma cell lines: KMS11, 26, 27, 28, RPMI8226, cultured alone, an increase in CD26 expression levels was observed within 24 hrs of the treatment with broad inhibitors: panobinistat, vorinostat or isoform-selective inhibitors: romidepsin (HDAC1i), BG45, entinostat, RG2833 (HDAC3i) and nexturastat A, tubastatin A, ricolinostat (HDAC6i) by flow cytometry...First, the expression level of c-Myc in KMS11, 27 and RPMI8226 was time-dependently decreased on treatment with panobinostat or RG2833 both at mRNA and protein levels... HDACi sensitizes myeloma cells with CD26 antigen loss to CD26mAb via c-Myc/Sp1-mediated CD26 induction and augments its cytotoxicity. Molecular markers, Multiple myeloma, MYC, Monoclonal antibody"

Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • DPP4 • HDAC3 • MYC • SDC1

HDAC1 mediates epithelial-mesenchymal transition and promotes cancer cell invasion in glioblastoma. (PubMed, Pathol Res Pract) - "The results showed that an HDAC1 inhibitor (RGFP109) could inhibit the EMT process in glioma cells in vitro, thereby affecting the invasion and migration of cells. Similar results were obtained based on in vivo studies. Our data suggest that HDAC1 has the potential to be a powerful prognostic biomarker, which might provide a basis for developing therapeutic targets for GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • HDAC1

HDAC Inhibition Involves CD26 Induction on Multiple Myeloma Cells Via the c-Myc/Sp1-Mediated Prompter Activation and Overcomes Therapeutic Resistance By Humanized Antibody (ASH 2022) - "Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), cultured alone, the increased expression in CD26 levels of MM cells was detectable within 24 hr of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA by flow cytometry... HDACi not only shows anti-MM activity itself but sensitizes MM cells with CD26 antigen loss to CD26mAb via c-Myc/Sp1-mediated CD26 induction and augments its cytotoxicity."

Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • DPP4 • HDAC3 • MYC

Inhibition of histone deacetylase with RG2833 mitigates spatial memory deficits and disease associated neuroinflammation in a transgenic rat model of Alzheimer’s Disease (Neuroscience 2022) - "These data indicate that histone modifying therapies can improve cognitive behavior by improving the expression of neuroprotective genes and by modulating the activation of immune cells and possibly dampening the inflammatory response. Based on our data, we propose that RG2833 could be an effective therapeutic to treat disorders such as AD."

Epigenetic controller • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Mental Retardation • Psychiatry • FOS

Combination of HDAC inhibitor and PI3K/mTOR inhibitor synergistically induces apoptosis in DIPG (SNO 2022) - "In vivo experiments evaluating the efficacy of combination treatment are in progress. Our data suggest the combination of RG2833 and paxalisib may be a promising treatment option for DIPG."

IO biomarker • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • BCL2 • BCL2L1 • CDKN1A • PARP1 • RB1 • XIAP

Epigenetic upregulation of Schlafen11 renders WNT- and SHH- activated medulloblastomas sensitive to cisplatin. (PubMed, Neuro Oncol) - "High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin."

Journal • Brain Cancer • Immunology • Medulloblastoma • Oncology • Solid Tumor • SLFN • SLFN11

Histone deacetylase 1 and 3 inhibitors alleviate colon inflammation by inhibiting Th17 cell differentiation. (PubMed, J Clin Lab Anal) - "HDAC1 and 3 inhibitors can modulate the differentiation of inflammatory Th17 cells, downregulate IL-17A levels, and exert anti-inflammatory effects in experimental colitis mice, indicating that HDAC1 and 3 may be potential therapeutic targets for patients with IBD."

Epigenetic controller • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • HDAC1 • IL17A

The PI3k inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors (ISPNO 2022) - No abstract available

Preclinical • Oncology • Rhabdoid Tumor • Sarcoma

The PI3k inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors (ISPNO 2022) - No abstract available

Preclinical • Oncology • Rhabdoid Tumor • Sarcoma

Isoform-selective HDAC inhibition up-regulates CD26 expression on multiple myeloma cells and augments cytotoxic efficacy by humanized monoclonal antibody (AACR 2022) - "Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), the increased expression in CD26 levels was detectable within 24 h of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA... Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells."

Clinical • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • DPP4 • HDAC1 • HDAC3

The PI3K inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors (AACR 2022) - "Additionally, our pilot combination study in orthotopic xenograft models of AT/RT demonstrated that combination therapy slows tumor growth more significantly than each agent alone and vehicle control (bioluminescent imaging). This novel combination therapy will readily translate into a new clinical trial aimed at improving survival in this deadly pediatric brain tumor."

Preclinical • Brain Cancer • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor

Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death (AACR 2022) - "Evaluation of combination treatment for apoptotic effects in vitro and in vivo are ongoing. These findings identify RG2833 and Paxalisib as a promising combination therapy for DIPG."

IO biomarker • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • BCL2 • BCL2L1 • CASP3 • CDKN1A • XIAP

KAZIA THERAPEUTICS ANNOUNCES PRECLINICAL DATA PRESENTED AT AACR CONFERENCE BY JOHNS HOPKINS UNIVERSITY SHOWING ACTIVITY OF PAXALISIB IN PAEDIATRIC BRAIN TUMOURS (PRNewswire) - "Kazia Therapeutics Limited...is pleased to announce new preclinical data demonstrating the activity of paxalisib in two forms of childhood brain cancer with very high unmet medical need....Data from Professor Rubens' laboratory shows that the PI3K pathway is commonly activated in AT/RT, and that treatment with paxalisib alone is active in preclinical models of the disease...Data from Drs Raabe and Barnett and colleagues identifies an additional novel treatment combination, with the HDAC inhibitor RG2833, which exhibits evidence of strong synergy in a preclinical model of DIPG."

Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor

[VIRTUAL] Brain penetrant HDAC inhibitor RG2833 induces DIPG cell death and synergizes with lomustine (AACR 2021) - "The pan-histone deacetylase (HDAC) inhibitor panobinostat showed great activity against DIPG in pre-clinical models, but has poor blood brain barrier penetration and demonstrated significant toxicity in clinical trials...RG2833 demonstrated cytotoxicity against temozolomide-resistant glioblastoma and downregulated the NFĸB pathway...We will next assess combination treatment in vitro and in vivo for apoptotic effects. This data indicates that selective HDAC inhibitor RG2833 may be a promising therapeutic candidate for DIPG."

IO biomarker • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor • BAX • BCL2 • BCL2L1 • CASP3 • RELA • XIAP