In human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, the most prevalent subtype, the pathological complete response (pCR) rate after neoadjuvant chemotherapy is less than 18 %, and the survival of patients with advanced-stage disease is approximately 34 %, highlighting the critical demand for more potent therapies. Recent research has underscored the substantial therapeutic benefits of the combination of CDK4/6 inhibitors and fulvestrant (Ful) in managing HR+/HER2- breast cancer. These therapeutics not only curtail tumor proliferation but also alter the tumor immune microenvironment, suggesting novel avenues for immunotherapy for this breast cancer subtype. Flow cytometry, PCR, WB, and RNA-seq experiments revealed that the combination of the CDK4/6 inhibitor palbociclib (Pal) with Ful upregulated CCL2 in tumor cells by inducing the SASP and activating the MAPK signaling pathway. CCL2 attracts Tregs to the tumor microenvironment, where it exerts an immunosuppressive effect. By administering the CCL2 inhibitor pirfenidone, we inhibited these effects and enhanced the antitumor efficacy of Pal + Ful. Our research revealed an immunosuppressive effect of CDK4/6 inhibitors and fulvestrant and suggested that CCL2 inhibitors may be a viable approach for treating patients with advanced HR+/HER2- breast cancer.

2024-12-01·CELLULAR SIGNALLING

MiR-24-3p modulates cardiac function in doxorubicin -induced heart failure via the Sp1/PI3K signaling pathway

Article

作者: Zeng, Linwen ; Zheng, Yonghong ; Yang, Chao ; Ke, Jun ; Yu, Huizhen ; Zhang, Jiancheng ; Xiang, Guojian

PURPOSE:

The goal of this research was to explore the role of miR-24-3p in heart failure (HF), with a focus on its impact on the specificity protein 1 (Sp1)/phosphoinositide 3-kinase (PI3K) pathway.

METHODS:

HF rat and HF cell models were established using doxorubicin(Dox). Cardiac function was assessed through echocardiography, while histological changes were observed via hematoxylin-eosin (HE) staining. To further investigate the underlying mechanisms, HF cell models were treated with either an Sp1 inhibitor or a PI3K inhibitor. Additionally, models with miR-24-3p overexpression or silencing were constructed. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined by ELISA. Cell apoptosis was evaluated using TUNEL staining, and lactate dehydrogenase (LDH) levels were measured by colorimetry. Reactive oxygen species (ROS) production was analyzed using flow cytometry. Related gene and protein expressions were assessed via qRT-PCR and Western blotting. Finally, the relationship between miR-24-3p and Sp1 was confirmed through dual-luciferase assays.

RESULTS:

Dox treatment increased the left ventricular internal diameter (LVIDd) while decreasing ejection fraction (EF) and fractional shortening (FS), leading to disorganized cardiomyocyte arrangement, cellular edema, and necrosis in rats. In HF rats, NT-proBNP, Caspase-3, and miR-24-3p expression levels were elevated, whereas Sp1 and PI3K mRNA and protein expression levels were decreased. Similarly, Dox-induced damage in H9c2 cardiomyocytes resulted in increased NT-proBNP, apoptosis, Caspase-3, LDH, ROS, and miR-24-3p expression, along with decreased Sp1 and PI3K expression. Treatment with either Sp1 or PI3K inhibitors exacerbated the Dox-induced cardiomyocyte damage, further elevating NT-proBNP, apoptosis, Caspase-3, LDH, ROS, and miR-24-3p expression levels. Notably, Sp1 inhibition reduced PI3K expression, and PI3K inhibition, in turn, suppressed Sp1 expression. Overexpression of miR-24-3p worsened Dox-induced cardiomyocyte damage, characterized by increased NT-proBNP, apoptosis, Caspase-3, LDH, and ROS expression, alongside reduced Sp1 and PI3K expression. In contrast, silencing miR-24-3p mitigated these detrimental effects and increased Sp1 and PI3K expression. Dual-luciferase assays confirmed that miR-24-3p directly targets Sp1.

CONCLUSION:

Dox induces cardiomyocyte damage, impairs cardiac function, and promotes cardiomyocyte apoptosis and oxidative stress. Silencing miR-24-3p offers a protective effect by activating the Sp1/PI3K signaling pathway in heart failure.

2024-12-01·BIOORGANIC CHEMISTRY

Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations

Article

作者: Alzahrani, Abdullah Yahya Abdullah ; Al-Karmalawy, Ahmed A. ; El-Dessouki, Ahmed M ; Al-Karmalawy, Ahmed A ; Moussa, Sana Ben ; El-Dessouki, Ahmed M. ; Tawfik, Haytham O. ; Tawfik, Haytham O ; Shaldam, Moataz A. ; Sharaky, Marwa ; Saleh, Mohamed M ; Mousa, Mai H.A. ; Saleh, Mohamed M. ; Mousa, Mai H A ; Shaldam, Moataz A

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful "multitarget-directed drug" for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.

项与 HSP90 inhibitors(JMackem) 相关的新闻（医药）

2024-09-26

·PRNewswire

Breakthrough Therapy Designation (BTD) for BioCity's SC0062, a selective endothelin type A (ETA) antagonist, granted by National Medical Products Administration for IgA nephropathy (IgAN) with proteinuria

SHANGHAI, Sept. 26, 2024 /PRNewswire/ -- BioCity Biopharma (BioCity) announced its endothelin receptor type A (ETA) selective antagonist SC0062 has been granted the Breakthrough Therapy Designation (BTD) by National Medical Products Administration (NMPA) for the treatment of IgA nephropathy (IgAN) with proteinuria. The BTD for SC0062 was granted based on the outstanding results in subjects with IgAN and proteinuria participating in a randomized double-blind, placebo-controlled Phase 2 trial known as 2-SUCCEED. The main objective of the 2-SUCCEED trial was to evaluate the efficacy and safety of SC0062 in individuals with two types of chronic kidney disease (CKD), IgAN and diabetic kidney disease (DKD). Treatment of IgAN with SC0062 resulted in a clinically meaningful and statistically significant reduction in proteinuria with a clear dose-response relationship and good safety profile. Peripheral edema occurred at a much lower rate in SC0062-treated subjects compared to that in the placebo group. Additionally, for subjects who were receiving concurrent treatment with SGLT2 inhibitors, the combination of SC0062 and SGLT2 inhibitors resulted in a favorable safety profile. These results will be presented at an upcoming scientific conference. The study is still ongoing in the DKD cohort, and these results are expected in Q4 of this year. As one of the most common primary glomerular diseases worldwide, many individuals with IgAN will progress to end-stage renal disease (ESRD) within 10 to 20 years, requiring renal dialysis or kidney transplantation. While developing novel treatments for CKD, especially IgAN, has become a global focus, there remains an unmet medical need for more effective and tolerable therapeutics that can be administered safely for many years to reduce the risk of progression to ESRD. In recent years, several studies have demonstrated that endothelin receptor antagonists can improve renal blood flow, reduce proteinuria, and alleviate inflammatory and fibrotic processes, making them a promising therapeutic option for treating IgAN and other forms of CKD. SC0062 is a novel, highly selective ETA antagonist designed for CKD and the results from a Phase 1 study of SC0062 in healthy volunteers and subjects with IgAN in the 2-SUCCEED study have demonstrated its potential to be the "best-in-class" endothelin antagonist in the treatment of IgAN or CKD. Currently, BioCity is planning Phase 3 clinical trials of SC0062 in China and worldwide with the objective of registering and marketing the agent in IgAN, DKD and other types of CKD. About SC0062 SC0062 is a novel and highly unique ETA antagonist due to its high selectivity for ETA over endothelin receptor B (ETB). The high ETA selectivity suggests that it has a greater potential than non-selective ET antagonists for reducing progression of CKD while avoiding the safety risks associated with other nonselective molecules in the same class. Preclinical studies have shown that SC0062 improves pathological scores in models of acute kidney injury and CKD. In the completed Phase I study, SC0062 demonstrated a favorable safety profile, good tolerability, and predictable pharmacokinetic characteristics. Fluid retention, an adverse event associated with non-selective ET antagonists due to undesirable ETB blockade, was not observed in the phase 1 trial in healthy volunteers nor in the IgAN cohort of the Phase 2 study. SC0062 is potentially a best-in-class ETA selective antagonist. The ongoing Phase 2 clinical study is designed to evaluate the efficacy and safety of SC0062 in patients with CKD with proteinuria. It is a multi-center, randomized, double-blind, placebo-controlled study with two parallel cohorts (IgAN and DKD). The trial is led by Professor Jianghua Chen, Director of the Kidney Disease Center at the First Affiliated Hospital of Zhejiang University School of Medicine and former Chairman of the Chinese Medical Association Nephrology Branch. The study is being conducted at over 40 study sites nationwide. The 2-SUCCEED study has fully enrolled all subjects in two cohorts. The primary endpoint in the IgAN cohort was met and based on this result SC0062 has granted BTD from NMPA, whereas the study is ongoing in the DKD cohort, and the results are expected in Q4 of this year. About BioCity Founded in December 2017, BioCity is a clinical-stage biopharmaceutical company committed to developing novel and highly differentiated, modality-independent therapeutics for cancer and autoimmune disorders including CKD. BioCity has established a pipeline of more than 10 innovative drug candidates, including small molecules, monoclonal and bispecific antibodies, and antibody-drug conjugates (ADC). Currently, BioCity's SC0062, a highly selective ETA antagonist, is in Phase 2 clinical development for CKD and a global Phase 3 registration trial is being planned. In addition, BioCity has five core oncology assets in Phase 1/2 clinical development, including first-in-class CDH3-targeting ADC and GPC3-targeting ADCs, WEE1 and ATR inhibitors targeting the DNA damage response (DDR) pathway, and a monoclonal antibody targeting TIM-3 in collaboration with AstraZeneca. For more information, please visit Or LinkedIn BioCity Biopharma Contact: [email protected] [email protected] SOURCE BioCity Biopharma WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED