NHWD-870 / Wenda Pharmaceutical - LARVOL DELTA

NHWD-870 suppresses tumor proliferation via the BRD4/STRADA/CCND1 axis in small cell lung cancer. (PubMed, Lung Cancer) - "NHWD-870 exhibits anti-tumor activity both in vitro and in vivo against SCLC, primarily by regulating the BRD4/STRADA/CCND1 axis and inhibiting the transition of the cell cycle from the G1 phase to the S phase. These findings highlight the therapeutic potential of NHWD-870 as a novel BET inhibitor for SCLC treatment and provide a molecular basis for further clinical development."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • BRD4 • CCND1

Inhibition of BRD4 sensitizes NSCLC cells to osimertinib by suppressing APT1 and promoting MST1 palmitoylation. (PubMed, Cell Death Discov) - "In our study, osimertinib-resistant HCC827/OR and PC-9/OR cells were established from parental osimertinib-sensitive cells, and osimertinib (AZD9291) and NHWD870, a bromodomain and extra-terminal (BET) inhibitor, were used to treat cells and mice. Inhibition of BRD4 sensitized non-small-cell lung cancer (NSCLC) cells to osimertinib by blocking YAP1-mediated APT1 transcription and disrupting APT1-mediated depalmitoyation of MST1 and YAP1 nuclear translocation, which restores osimertinib sensitivity through the APT1-MST1-YAP1 axis in NSCLC. Our study provides a novel mechanism of osimertinib resistance and suggests potential therapeutic strategies for NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRD4 • EGFR • FAS • YAP1

BET INHIBITOR NHWD-870 INHIBITED CANCER PROGRESS VIA MODULATING MYCN PHASE SEPARATION IN NEUROBLASTOMA (SIOP 2025) - "These results provide a mechanistic framework for the therapeutic potential of targeting MYCN phase separation in high-risk NB."

Neuroblastoma • Oncology • Solid Tumor • BRD4 • MYC • MYCN

Targeting CLEC4E in immunosuppressive tumour-associated macrophages via BET inhibition. (PubMed, Clin Transl Med) - "CLEC4E+ TAMs promote an immunosuppressive microenvironment by enhancing their own proliferation and impairing anti-tumour functions, thereby limiting T-cell cytotoxicity. Targeting the BRD4/CEBPβ/CLEC4E axis with BET inhibitors represents a promising therapeutic strategy for reprogramming TAMs and enhancing anti-tumour immunity."

IO biomarker • Journal • Melanoma • Oncology • Ovarian Cancer • Solid Tumor • BRD4 • GZMB

Complete Response to BET Inhibitor in Primary Pulmonary NUT Carcinoma With Single-Cell Sequencing-Based Analysis: A Case Report. (PubMed, JTO Clin Res Rep) - "This suggests that NHWD-870 exerts its effects through both direct tumor suppression and modulation of the immune microenvironment. This case highlights the exceptional efficacy of BET inhibitors in the treatment of NUT carcinoma, as evidenced by the first report of complete response achieved with BET inhibitor monotherapy, and supports their potential as a personalized therapeutic strategy."

Journal • Lung Cancer • NUT Midline Carcinoma • Oncology • CD8

Restoration of Osimertinib sensitivity in lung cancer through BRD4 inhibitor-mediated depalmitoylation of mutant EGFR via APT1. (PubMed, NPJ Precis Oncol) - "Importantly, BRD4 inhibitor NHWD870 significantly reversed this resistance by inhibiting the nuclear translocation of EGFR and subsequent transcriptional activation of CMPK2. In conclusion, BRD4 inhibitor inhibited APT1-mediated depalmitoylation modification of EGFR, resulting in reduction of nuclear EGFR and subsequent downregulation of CMPK2, enhancing Osimertinib sensitivity in NSCLC. This study provides a novel therapeutic strategy for overcoming Osimertinib resistance in NSCLC treatment."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRD4 • EGFR • FAS

BET inhibitor in combination with BCG vaccine enhances antitumor efficacy and orchestrates T cell reprogramming for melanoma. (PubMed, Cell Rep Med) - "Here, we show that a combination of bromodomain and extra-terminal protein family inhibitor, NHWD-870, and Bacillus Calmette-Guérin vaccine is a promising therapeutic strategy for melanomas...Furthermore, our findings are reinforced by a humanized patient-derived xenograft (PDX) model, which exhibits notable antitumor effects in humanized tumor-bearing mice treated with the combination therapy. Our study underscores the immense potential of this therapeutic approach for clinical practice, offering promising prospects in overcoming the limitations of current treatments."

Journal • Melanoma • Oncology • Solid Tumor • BRD4

TME-responsive nanocomposite hydrogel with targeted capacity for enhanced synergistic chemoimmunotherapy of MYC-amplified osteosarcoma. (PubMed, Bioact Mater) - "To address the above issues, we developed an injectable TME-responsive nanocomposite hydrogel to simultaneously deliver an effective MYC inhibitor (NHWD-870) and IL11Rα-targeted liposomes containing cisplatin-loaded MnO2 (Cis/Mn@Lipo-IL11)...In the osteosarcoma-bearing model, the nanocomposite hydrogel significantly enhanced tumor T cell infiltration, induced effective anti-tumor immunity and attenuated lung metastasis. Therefore, our results reveal a powerful strategy for targeted combination therapy of MYC-amplified osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CCL2 • IL13 • MYC

Compassionate Use Study of NHWD-870 in Patients With Advanced Solid Tumors or Lymphomas Carrying NUT Rearrangement (clinicaltrials.gov) - P=N/A | N=30 | Recruiting | Sponsor: Hunan Province Tumor Hospital | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Real-world • Real-world evidence • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

A Multicenter, Open-label, Single-arm, Phase II Study of NHWD-870 HCl in Adults and Adolescents With Advanced NUT Cancer (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: Zhejiang Wenda Medical Technology Co., Ltd.

Metastases • New P2 trial • NUT Midline Carcinoma • Oncology

Primary thyroid nuclear protein in testis carcinoma: a case report and literature review. (PubMed, Gland Surg) - "The patient was treated with a combined regimen of radiotherapy of 70 Gy, chemotherapy with paclitaxel (albumin-bound), immunotherapy with nivolumab, targeted therapy with anlotinib and BET inhibitor NHWD-870, but the patient died 7 months after diagnosis. Gene rearrangement detection is also helpful for diagnosis and treatment. At present, surgery and radiation are still first choices for NC, and advances in targeted immunotherapy such as bromodomain and end motif inhibitors (BETi) may bring better treatment options to patients."

IO biomarker • Journal • Review • Endocrine Cancer • Gastrointestinal Disorder • Musculoskeletal Pain • NUT Midline Carcinoma • Oncology • Pain • Solid Tumor • Testicular Cancer • Thyroid Gland Carcinoma • NSD3 • NUTM1 • TP63

A BET inhibitor, NHWD-870, can downregulate dendritic cells maturation via the IRF7-mediated signaling pathway to ameliorate imiquimod-induced psoriasis-like murine skin inflammation. (PubMed, Eur J Pharmacol) - "While NHWD-870 could inhibit IRF7 and phosphorylated-IRF7 expression in vivo and in vitro. These results indicate that NHWD-870 suppresses the maturation and activation of DCs by decreasing IRF7 proteins which finally alleviates psoriasis-like skin lesions, and NHWD-870 may be a potent therapeutic drug for psoriasis."

IO biomarker • Journal • Preclinical • Dermatitis • Dermatology • Immunology • Inflammation • Oncology • Psoriasis • CD40 • CD80 • CD86 • CXCL10 • CXCL9 • IL1B • IL23A • IL6 • IRF7 • TNFA

Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1. (PubMed, Theranostics) - "Thus, we screened for inhibitors that repress YAP1 expression and identified multiple bromodomain and extra-terminal (BET) inhibitors, including NHWD-870, as hits. We identified a new vulnerability for MEK inhibitor-resistant melanomas, which activated Hippo pathway due to elevated YAP1 activity. Inhibition of BRD4 using BET inhibitors suppressed YAP1 expression and led to blunted melanoma growth when combined with treatment with the MEK inhibitor trametinib."

Journal • Melanoma • Oncology • Solid Tumor • BRAF • BRD4 • YAP1

IL1R2 promotes retinal angiogenesis to participate in retinopathy of prematurity by activating the HIF1α/PFKFB3 pathway. (PubMed, Exp Eye Res) - "Moreover, NHWD-870 (a HIF1α/PFKFB3 pathway inhibitor) suppressed endothelial cell migration, angiogenesis, and proliferation induced by IL1R2 overexpression. In conclusion, IL1R2 facilitates the migration, angiogenesis, and proliferation of choroidal endothelial cells by activating the HIF1α/PFKFB3 pathway to regulate ROP progression."

Journal • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • HIF1A • IL1R2 • PFKFB3

Compassionate Use Study of NHWD-870 in Patients With Advanced Solid Tumors or Lymphomas Carrying NUT Rearrangement (clinicaltrials.gov) - P=N/A | N=30 | Recruiting | Sponsor: Hunan Province Tumor Hospital

Metastases • New trial • Real-world • Real-world evidence • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

NHWD-870 protects the kidney from ischemia/reperfusion injury by upregulating the PI3K/AKT signaling pathway (experimental study). (PubMed, J Med Life) - "NHWD-870 demonstrated substantial nephroprotective effects in reducing renal damage induced by ischemia-reperfusion injury in rats. These effects may be attributed to the anti-apoptotic properties, as indicated by increased levels of the anti-apoptotic protein Bcl-2, and the reduction in oxidative stress marker PGF-2 through upregulation of the PI3K/AKT signaling pathway, along with the decrease in the inflammatory marker IL-1B."

IO biomarker • Journal • Acute Kidney Injury • Cardiovascular • Lymphoma • Nephrology • Oncology • Renal Disease • Reperfusion Injury • BCL2 • BRD4 • IL1B

The novel BRDT inhibitor NHWD870 shows potential as a male contraceptive in mice. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Our results show that NHWD870 can induce a complete and reversible contraceptive effect in mice, which is stronger than that of JQ1 and its synthesized derivatives. This study is expected to eventually lead to clinical trials."

Journal • Preclinical • Infertility • Oncology • Sexual Disorders • BRDT

The binding mechanism of NHWD-870 to bromodomain-containing protein 4 based on molecular dynamics simulations and free energy calculation. (PubMed, Phys Chem Chem Phys) - "NHWD-870 showed a similar binding affinity for BD1 and BD2 of BRD4. Binding free energy calculations for the R/S conformations of NHWD-870 suggest that the chiral centre of NHWD-870 may confer similar roles upon the R and S conformations for binding with BRD4, facilitating the identification of novel BRD4 inhibitors."

Journal • Oncology • BRD4

Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling. (PubMed, Front Oncol) - "Finally, we confirmed the efficacy of synthetic lethal effects of NHWD-870 and cisplatin in antagonizing osteosarcoma in a preclinical PDX model. Taken together, these findings demonstrate that NHWD-870, as an effective BET inhibitor, may be a potential candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity. In addition, NHWD-870 appears to be a promising therapeutic strategy for bone-associated tumors, as it interferes with the vicious cycle of tumor progression and bone destruction."

Journal • Oncology • Osteoporosis • Osteosarcoma • Sarcoma • Solid Tumor • BRD4 • GP130

NHWD-870, a novel BET family bromodomain inhibitor targeting BRD4, proved to be effective and promising for treatment of small cell lung cancer (AACR 2018) - "Previous study show that BRD4 was unregulated in different kind of cancer, with leukemia included, and BETi (BET inhibitors), such as JQ1(+) show evidence to inhibit the proliferation of cancer in vitro and vivo. Monotherapy and combining with antiangiogenesis, such as bevacizumab and apatinib, NHWD-870 and NHWD-870-HCL proved to be more effective in SCLC cell lines and PDX in patients who show resistant to double Platinum chemotherapy with etoposide and cisplatin.Conclusion, NHWD-870 shows to be a powerful anti-cancer drug in SCLC. Further basic and clinical research should be conducted from bench to beside."

IO biomarker • Leukemia • Small Cell Lung Cancer

Cellular pharmacokinetics and molecular pharmacodynamics studies of a novel BET inhibitor NHWD870 in sensitive and resistant leukemic cell lines (AACR 2018) - "NHWD870 intracellular accumulation occurred to a similar extent and timing in NHWD870 sensitive and resistant leukemic cell lines. Rapid modulation of NHWD870-target genes was observed at the protein levels only in sensitive cell lines."

IO Biomarker • PK/PD data • Preclinical • Acute Lymphocytic Leukemia • Chronic Myeloid Leukemia

Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. (PubMed, Nat Commun) - "Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors."

Journal • Oncology • Solid Tumor

New cancer drug shrinks tumors, reduces side effects, in animal studies (Yale News) - "Unlike other BET inhibitors, NHWD-870 exhibited robust activity against solid tumors, partly by preventing tumor-associated macrophages (TAMs), or large white blood cells in the immune system, from proliferating, the researchers found....NHWD-870 also had lower toxicity, as measured in bodyweight loss in animals, than other inhibitors."

Preclinical • Oncology • Solid Tumor

Pancreatic Cancer Organoids for Determining Sensitivity to Bromodomain and Extra-Terminal Inhibitors (BETi). (PubMed, Front Oncol) - "Primary organoids from 24 PDAC patients were treated with NHWD-870 or JQ1, two inhibitors of c-MYC transcription. Notably, the comparison of their effect between the two sub-groups showed that both compounds are more efficient in MYC-high than in MYC-low samples, being NHWD-870 the more potent treatment. In conclusion, this study shows that the molecular signatures could be applied to organoids obtained directly from PDAC patients to predict the treatment response and could help to take the more appropriate therapeutic decision for each patient in a clinical timeframe."

Journal

Novel BETi NHWD-870 synergizes with immune checkpoint inhibitor in preclinical model of non-small cell lung cancer (AACR 2019) - "We established a useful method to evaluate tumor response to immune checkpoint inhibitor. And our data proved BETi plus immune checkpoint inhibitor to be a promising treatment of NSCLC."

Checkpoint inhibition • Preclinical