molibresib (GSK525762)

When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.

Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment.

P1, N=124, Terminated, GlaxoSmithKline | Phase classification: P1/2 --> P1

ChIP-PCR and ChIP-seq analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-Fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the BET inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth...Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell-targeting agents for gastric cancer treatment.

BRD4 inhibition by JQ-1 and I-BET-762 or BRD4 knockdown resulted in substantial accumulation of reactive oxygen species (ROS) in both HEK293T and HeLa cells. Our results suggest that ROS accumulation and FSP1 downregulation are common mechanisms underlying increased ferroptosis with BRD4 inhibitors. Thus, BRD4 inhibitors might be more effective in combination with ferroptosis inducers, especially in FSP1-dependent cancer cells.

RNAseq analysis demonstrated that the inhibitors increased viral E1A expression, altered expression of cell cycle regulators and inflammatory factors, and attenuated expression levels of tumour cell oncogenes such as c-Myc and Myb. The data suggest that the tumour-selective Ad∆∆ and Ad-3∆-A20T combined with epigenetic inhibitors is a novel strategy for the treatment of PDAC by eliminating both cancer and associated stromal cells to pave the way for immune cell access even after systemic delivery of the virus.

Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study. Copy number adjusted ctDNA MR is a promising early marker for clinical benefit. Clinical trial information: NCT02964507.

Moreover, molibresib and dasatinib showed a cooperative effect in suppressing the proliferation of BRD4-high GC cells. In conclusion, we confirmed that increased epithelial BRD4 expression is associated with poor disease stage and prognosis in GC and BRD4 blockage might be a valuable strategy to improve the sensitivity of dasatinib and other drugs in the chemotherapy of advanced GC.

F) Cell-line sensitivity ranking based on IC50 values of I-BET-762. G) Overall and event free survival curves of KMT2A positive patients in TARGET AAML1031 and AML0531 based on ssGSEA scoring of genes downregulated by the I-BET-762 treatment.

Steroids, Colchine, Azathioprine (Aza) and interferon α are commonly used for BD management [Hatemi G. Ann Rheum Dis 2018]...The aims of the present work were to: 1) evaluate the effects in vitro on NKG2D expression by immune cells of drugs used for BD management, epigenetic drugs and nutraceuticals; 2) determine if the effects differed between BD patients and controls (CTR); 3) analyse circulating levels of NKG2D ligands. Peripheral Blood Mononuclear Cells (PBMCs) from 5 active BD patients naive from therapy and 5 CTR were treated for 48h with 500 ng/ml Dexamethasone (Dexa) or 3000U interferon α-2A or 1µM Colchicine or 30µM Aza or 250µM iBet-762 or 730µM Valproic Acid or 5µM Curcumin... BD patients were characterized by higher soluble MICA that increases the possibility of immune cell activation. Drugs commonly used for BD management were able to down-regulate NKG2D levels on immune cells surface, reducing their activation capacity. In addition drugs used for the treatment of other diseases, such as Valproic Acid used for breast cancer and iBet-762 used for pancreatic cancer, showed the same effects on NKG2D expression.

Thus far, Cell Titer Glo assays have been performed in triplicate for both Cal-27 and OECM-1 to analyze their viability in the presence of four drugs used to treat other forms of cancer with different mechanisms of action: PD0, a MEK inhibitor, IBET-762, a BET inhibitor, ABT-199, a Bcl-2 inhibitor, and JQ1, a BRD4 inhibitor...The drugs that will be used include: Cisplatin, 5-FU, Taxol, Docetaxel, Hydroxyurea, Methotrexate, Bleomycin, Gemcitabine, and Vincristine, all of which interfere with DNA synthesis and cell growth...Some of these drugs include: Gefitinib, a EGFR inhibitor, Venetoclax, a BCL-2 inhibitor, Irinotecan, a topoisomerase inhibitor, Mitoxantrone, a topoisomerase 2 and PKC inhibitor, and several other drugs. Cellular responses will then be assessed to determine if any combinations are synergistic. The data generated can aid researchers in understanding how different OSCC cells respond to drug combinations, which may lead to more successful clinical treatment options in the future.

In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from PBMCs of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multi-agent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients, and expands the potential treatments for this recalcitrant malignancy.

GSEA revealed that gene expression changes with molibresib varied by patient, response status, and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.

BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.

P1/2, N=123, Active, not recruiting, GlaxoSmithKline | Phase classification: P2 --> P1/2

Finally, we used the Computational Analysis of Resistance (CARE) database to identify specific gene-associated drugs for RR patients and found that GSK525762A and nilotinib might be promising candidates for RR treatment. Taken together, these results demonstrate that B cells in TME may have a significant impact on the RT and that these two drug candidates, GSK525762A and nilotinib, might be helpful for the treatment of RR patients.

In addition, the compounds exhibited cytotoxic effects against gastric cancer cell lines which were resistant to I-BET-762, a BET bromodomain inhibitor. In conclusion, the novel scaffold to suppress brd4 activity was effective against cancer cells both in vitro and in vivo.

We indicate that drug synergy between I-BET762 and Talazoparib is associated with the attenuation HR-DSBR process and the downregulation of various players of DNA damage response by BET inhibition, such as CHEK2, PTEN, NBN, and FANCC. Our results provide a rationale for the development of new combinatorial strategies for the treatment of SCLC.

Three human PCa cell lines, PC-3, LNCaP, and C42B, were selected and treated with IC50 value of I-BET762, I-BET726, and CPI-203, respectively. PCa is closely related to histone crotonylation. Inhibition of BRD4 expression can inhibit the proliferation, migration, and invasion of PCa cells.

In addition, cross-resistance to other FGFR inhibitors infigratinib, pemigatinib, derazantinib and AZD4547 was observed. In conclusion, we show that multiple factors contribute to the development of resistance against erdafitinib in an FGFR2-mutant endometrial carcinoma cell line. BET-bromodomain inhibitors are of potential interest as therapeutic agents to overcome resistance against FGFR inhibitors.

Materials & WM cells were treated with BET inhibitors (JQ-1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.

This study discloses that LAGE3 plays an oncogenic and cancer-immunological role, also providing novel PTC biological and clinical implications.

The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.

We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells...In addition, in vivo studies using a model of multiple brain metastasis (BM) showed improved survival with the combination of radiation + BET inhibitor (iBET-762) + VRB (75% long-term survivors, P < 0.05)...Overexpression of MZF-1 decreases TUBB3 expression and reduces BM in vivo, whereas its knockdown increases TUBB3 expression in breast cancer cells. In summary, this study demonstrates a regulatory mechanism of TUBB3 and provides support for an application of BET inhibition to sensitize breast cancer metastases to VRB-mediated therapy.

Our screening analysis revealed that JQ1 and IBET-762, inhibitors of epigenetic reader BRD4, and LBH589, a pan inhibitor of histone deacetylases (HDACs), exhibited synergy with VS-6063 in mitigating tumor cell viability. Finally, we showed that the effect of the VS-6063/JQ1 combination was nearly equivalent to that of VS-6063 plus Carboplatin or Osimertinib. Overall, our study indicates that the integrin/FAK and BRD4/c-Myc axes cooperatively drive NSCLC virulence, and a co-targeting may provide a line of therapy capable of overcoming EGFR/KRAS-driven malignancy.

P2, N=123, Active, not recruiting, GlaxoSmithKline | Trial completion date: Sep 2020 --> Aug 2021

P2, N=123, Active, not recruiting, GlaxoSmithKline | Trial completion date: Mar 2021 --> Sep 2020 | Trial primary completion date: Mar 2021 --> Sep 2020

P2, N=111, Completed, GlaxoSmithKline | Active, not recruiting --> Completed

Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Research Funding: GSK, Other Foundation

Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.

P2, N=123, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | N=294 --> 123

P2, N=110, Active, not recruiting, GlaxoSmithKline | Trial completion date: Oct 2023 --> Apr 2020 | Trial primary completion date: Jan 2023 --> Apr 2020

P1/2, N=196, Completed, GlaxoSmithKline | Active, not recruiting --> Completed

P2, N=294, Recruiting, GlaxoSmithKline | Trial completion date: Sep 2022 --> Feb 2021

P2, N=110, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting