MKC8866 / MannKind, Fosun Pharma - LARVOL DELTA

Environmental benzophenone exposure promotes liver cancer cell proliferation via the IRE1α-XBP1s pathway. (PubMed, Food Chem Toxicol) - "XBP1 was knocked down using siRNA, and the IRE1α-XBP1 pathway was inhibited with MKC8866...Mechanistically, 4HBP disturbed proteostasis and activated the IRE1α-XBP1s axis of the unfolded protein response (UPR) in HCC cells, which was critical for their increased aggressiveness. Collectively, these findings alert that environmental benzophenone exposure may increase the risk of HCC progression."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • XBP1

Integrating machine learning and structure-based simulations to prioritise Z4P as a mutation-resilient IRE1α inhibitor for breast cancer. (PubMed, Sci Rep) - "Docking studies revealed that Z4P exhibited the strongest binding affinity (- 7.93 kcal/mol) to the wild-type IRE1, compared with the control drug MKC8866 (- 6.7 kcal/mol)...MD simulations over 200 ns confirmed the stability of the IRE1-Z4P complex, with favourable RMSD, RMSF, Rg, and SASA profiles relative to the control. These findings highlight Z4P as a promising mutation-resilient IRE1 inhibitor and validate the effectiveness of the integrated computational pipeline for identifying potential anti-cancer therapeutics."

Journal • Breast Cancer • Oncology • Solid Tumor • ERN1

Therapeutic Targeting of Mutant p53–Driven UPR Addiction Overcomes ER Stress Resistance in Metastatic Prostate Cancer (EACR 2026) - "ER stress was induced using thapsigargin (Tg)...Adaptive UPR branches were modulated using Ceapin (ATF6 inhibition), MKC8866 (IRE1a inhibition) and ISR modulators. Mitochondrial survival buffering was disrupted using the clinically advanced BCL2/BCL-XL inhibitor Navitoclax... Metastatic TP53-mutant PCa exhibits mutp53-driven UPR addiction that can be therapeutically exploited. Combining mutp53 targeting strategies with clinically relevant UPR or BCL2 family inhibitors represents a rational approach to overcome ER stress resistance in mPCa."

IO biomarker • Metastases • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Psychiatry • Solid Tumor • ATF4 • ATF6 • BCL2L1 • CDC37 • ENTPD5 • PPP1R15A • TP53

Tumor-intrinsic IRE1α signaling drives immune evasion and resistance to immune checkpoint inhibitor in lung cancer by upregulating PD-L1 and remodeling the tumor microenvironment (AACR 2026) - "Notably, this pro-tumorigenic secretome was abrogated by the IRE1α inhibitor MKC8866...Collectively, tumor-intrinsic IRE1α orchestrates immune evasion in NSCLC by amplifying tumor-intrinsic PD-L1 expression through the IFNγ-STAT1-XBP1s-IRF1 axis and remodeling the TME via chemokines such as CCL20 that recruit immunosuppressive cell populations. The combination of an IRE1α inhibitor and anti-PD-1 antibody represents a promising strategy to enhance the efficacy of immunotherapy for NSCLC."

Biomarker • Checkpoint inhibition • IO biomarker • Tumor microenvironment • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCL20 • CD8 • ERN1 • IFNG • IRF1

Targeting IRE1α alleviates the immunosuppressive tumor microenvironment in prostate cancer (AACR 2024) - "Furthermore, IRE1α inhibition by the small molecule MKC8866 (ORIN1001) that is in clinical trials significantly enhanced anti-PD-1 checkpoint inhibitor therapy in mice. Our findings indicate that IRE1α not only promotes cancer cell growth and survival, but it also strongly inhibits anti-tumor immunity in the PCa TME."

Biomarker • IO biomarker • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Gynecological Cancers: A Narrative Review. (PubMed, Cureus) - "Therapeutically, IRE1 RNase inhibitors (e.g., MKC-8866, B-I09), PERK/EIF2AK3 pathway modulators, protein-disulfide isomerase inhibition, and agents that trigger irrecoverable ER stress show preclinical efficacy, including synergy with platinum, poly (ADP-ribose) polymerase (PARP) inhibitors, HDAC6 blockers, and PD-1 inhibitors...Thus, ER-stress/UPR signaling is a convergent, targetable axis in gynecologic cancers. Priorities include validating UPR-based prognostic signatures, defining context-specific vulnerabilities (e.g., genotype-informed IRE1/XBP1 dependence), and executing biomarker-driven clinical trials that combine UPR-targeted agents with standard chemotherapy, PARP inhibition, and immunotherapy to overcome resistance and improve patient outcomes."

IO biomarker • Journal • Review • Cervical Cancer • Endometrial Cancer • Epithelial Ovarian Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • ATF4 • ATF6 • EIF2AK3 • ERN1 • HSPA5 • XBP1

Combined effects of IRE1 inhibition and temozolomide in glioblastoma mouse models: potential mechanisms of action (EANO 2025) - "The mechanisms underlying this survival benefit are however unknown and need further investigation.Material and We performed a multi-omics integrative analysis (RNA-seq, WES) on two preclinical syngeneic mouse models (GL261 cells in C57BL/6 mice), testing two pharmacological inhibitors of IRE1: MKC8866 targeting its RNase activity and B4-7 targeting its kinase activity. Using preclinical models of GB and drugs targeting different activities of IRE1, we show that IRE1 inhibition combined with TMZ leads to enhanced mouse survival. The analysis of tumor exome and transcriptome suggests a link between IRE1 and the DNA repair system. These results reinforce the idea that IRE1 inhibition could be of strong therapeutic interest."

Preclinical • Tumor mutational burden • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ERN1 • TMB

Ire1 inhibitors attenuate Candida albicans pathogenicity and demonstrate potential for application in antifungal therapy. (PubMed, Front Microbiol) - "Three candidate inhibitors-MKC8866, STF083010, and 4μ8c-were predicted to interact with Ire1, but only 4μ8c exhibited consistent inhibitory activity. These findings demonstrate that pharmacological targeting of the UPR pathway through Ire1 inhibition is feasible. 4μ8c emerges as a promising candidate that diminishes the adaptability and pathogenicity of Candida albicans, offering new insights into antifungal therapeutic development."

Journal • Infectious Disease • ERN1

Endoplasmic Reticulum Stress Inhibits the Neuronal Differentiation of Human Stem Cells From Apical Papillae by Attenuating the Activity of ERK-IRE1α Axis In Vitro. (PubMed, Int Endod J) - "Severe ER stress inhibits the neuronal differentiation of SCAPs via decreasing ERK1/2 and IRE1α activity, whereas ER stress at an appropriate level is essential for the neuronal differentiation of SCAPs."

Journal • Preclinical • Transplantation • ERN1

The role of endoplasmic reticulum stress in BPS-induced disruption of endometrial decidualization. (PubMed, Ecotoxicol Environ Saf) - "ER stress inhibitors (TUDCA and MKC8866) mitigated these effects and restored decidualization markers. Our findings suggest that BPS contamination may contribute to implantation failure by disrupting HESC decidualization through ER stress activation."

Journal • Infertility • Sexual Disorders • ATF4 • IGFBP1 • XBP1

IRE1 signalinig in Triple Negative Breast Cancer (EACR 2025) - "Material and Omics datasets encompassing mRNA, miRNA, proteins, and metabolic products were generated from the TNBC cell line MDA-MB-231 following treatment with MKC8866, an IRE1 inhibitor, at multiple time points... We focused on identifying novel downstream targets of IRE1/XBP1 and IRE1/RIDD signaling pathways. We believe that our work will aid in deciphering the role of IRE1 in TNBC progression and characterization."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • ERN1 • XBP1

IRE1 activity regulates tumour and microenvironment cell lineage states while stratifying localised and metastatic prostate cancer (EACR 2025) - "We pharmacologically and physiologically perturbed AR (Charcoal Strip, R1881, Enzalutamide), IRE1 and Stress Responses (MKC8866, Thapsigargin, Tunicamycin, glutamine deprivation) in these lines as well as in P20-11 organoids carrying out single cell (scRNAseq) and bulk RNAseq. We have observed that IRE1 activity plays a crucial role in inflammatory responses, the balance between basal, luminal and club epithelial cell states and the responses of individual tumours to ADT and other therapies. Consequently, IRE1 modulation is worth exploring as differentiation therapy in PCa."

Late-breaking abstract • Metastases • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ERN1 • XBP1

The activity of the Unfolded Protein Response Transducer IRE1 is a predictor of treatment resistant disease and a proxy of NEPC and RB1-loss like phenotypes (PCF 2024) - "We pharmacologically and physiologically perturbed AR (Charcoal Strip, R1881, Enzalutamide), IRE1 and Stress Responses (MKC8866, Thapsigargin, Tunicamycin, glutamine deprivation) in these lines as well as in P20-11 organoids carrying out single cell (scRNAseq) and bulk RNAseq. We have generated an IRE1-dependent transcriptomic score as proxy of multiple driving biologies (AR, Inflammation, DNA repair, Cell Cycle, EMT), multiple histological features (stroma, varying histological tumour grades, varying benign structures, PIN), and can prognosticate bulk datasets from large cohorts both in localised (TCGA) and metastatic (PCF/SU2C) cohorts (CamCapp, cBIOPORTAL). This score may be used as a tool alongside imaging AI and other multiomic modalities to inform neoadjuvant therapeutic formulations."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ERN1 • RB1 • XBP1

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer. (PubMed, Nat Commun) - "Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa."

Biomarker • Journal • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia. (PubMed, Genes Immun) - "These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm."

IO biomarker • Journal • CNS Disorders • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • TLR7 • TLR8 • XBP1