CADD522 / University of East Anglia, University of Maryland Medical System - LARVOL DELTA

RUNX2 inhibitor CADD522 improves bone microarchitecture and lipid metabolism in post-menopausal bone loss. (PubMed, NPJ Drug Discov) - "Cross-species pharmacokinetic and toxicological studies demonstrated oral bioavailability, favourable short-term tolerability and target engagement despite rapid systemic clearance, while cellular thermal shift assays confirmed direct engagement of RUNX2. Together, these findings identify RUNX2 inhibition as a therapeutic strategy that simultaneously improves skeletal integrity and metabolic homeostasis, supporting further development of CADD522 for osteoporosis and other RUNX2-driven diseases."

Journal • Metabolic Disorders • Obesity • Oncology • Osteoporosis • Rheumatology • RUNX2

RUNX2 promotes chromatin accessibility and WNT signaling in inflamed intestinal epithelial cells. (PubMed, Mucosal Immunol) - "RUNX2 inhibition using CADD522 reduced β-catenin levels in 3D colonoids and restored VIL1 expression and junctional β-catenin localization in 2D cultures. These findings reveal an intrinsic defect in epithelial renewal in UC, driven in part by RUNX2-dependent WNT dysregulation. Our study identifies RUNX2 as a transcriptional regulator of epithelial stem cell function and WNT signaling in the inflamed human colon."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mucositis • Ulcerative Colitis • CTNNB1 • OLFM4 • RUNX2 • VIL1

RUNX2 drives adenoma-to-carcinoma transition in colon cancer. (PubMed, Cell Death Dis) - "The RUNX2-specific inhibitor CADD522 suppressed RUNX2 expression in vitro and inhibited the adenoma-to-adenocarcinoma transition in the AOM/DSS model...Multiplex immunofluorescence confirmed a close spatial association between CD8+PD-1+ Tex cells and RUNX2+ EPCs. In summary, CD8+ Tex cells may activate RUNX2 in malignant EPCs through TNF-α binding to TNFRSF1A, promoting the adenoma-to-carcinoma transition and contributing to poor prognosis."

IO biomarker • Journal • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • CD8 • PD-1 • RUNX2 • TNFRSF1A

RUNX2 inhibition alters PAX3::FOXO1 driven fusion-positive rhabdomyosarcoma cell state and growth (AACR 2024) - "RUNX2 is a vulnerability in RMS based on in silico, in vitro, and in vivo investigation, and may act to prevent osteogenic and myogenic differentiation via protein-protein relationships in the Hippo pathway. The next step will be assessing mechanistic relationships between the Hippo pathway and RUNX2, as well as the genome wide changes upon RUNX2 LOF by performing ChIP-seq, RNA-seq, and scRNA-seq experiments."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • PAX3 • RUNX2 • TAFAZZIN

RUNX2 Activation in Fibro/Adipogenic Progenitors Promotes Muscle Fibrosis in Muscular Dystrophy. (PubMed, Adv Sci (Weinh)) - "Additionally, we demonstrated that CADD522, a RUNX2 inhibitor, protects against muscle fibrosis in both dystrophic and denervated mice. Importantly, the anti-inflammatory drug prednisolone alleviated muscle fibrosis in MD patients by inhibiting inflammatory cytokine-mediated RUNX2 activation. Collectively, our findings indicated that the TGF-β-RUNX2 axis is a viable target for alleviating muscle fibrosis and related diseases, highlighting potential future research directions."

Journal • Fibrosis • Immunology • Inflammation • Muscular Dystrophy • RUNX2 • TGFB1

RUNX2 promotes epigenetic WNT signaling in inflamed intestinal epithelial cells. (PubMed, bioRxiv) - "RUNX2 inhibition using CADD522 reduced β-catenin levels in 3D colonoids and restored VIL1 expression and junctional β-catenin localization in 2D cultures...Elevated β-catenin and reduced OLFM4 and VIL1 expression indicate impaired self-renewal and differentiation. Pharmacologic inhibition of RUNX2 restores epithelial maturation, identifying RUNX2 as a key regulator of epithelial dysfunction in UC."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mucositis • Ulcerative Colitis • OLFM4 • RUNX2 • VIL1

EXPLORING THE DRIVING EFFECT OF CD8+ EXHAUSTED T CELLS ON MALIGNANT ADENOMA EPITHELIAL CELLS THROUGH RUNX2 BASED ON SINGLE-CELL TRANSCRIPTOME SEQUENCING (UEGW 2025) - "Both in vivo and in vitro experiments confirmed that RUNX2 promotes the proliferation, invasion, and migration of the HCT116 colon cancer cell line, while the RUNX2 inhibitor CADD522 can suppress the adenoma-to-carcinoma transition... This study identifies that CD8+ Tex cells may activate the transcription factor RUNX2 in colon cancer cells by binding the ligand TNF-α to the TNFR1 receptor on the membrane of malignant epithelial cells. This activation promotes the transition of malignant epithelial cells in colon adenomas to malignant cancer cells, leading to poor prognosis in COAD. This finding not only elucidates the key cellular and molecular mechanisms of the adenoma-to-carcinoma transition but also provides new potential targets for early intervention and treatment of colon cancer."

IO biomarker • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ANXA2 • CD8 • CEBPB • MAT2A • NOTCH1 • RUNX2 • SERPINE2 • STAT1 • TNFA • TNFRSF1A

RUNX2 inhibition disrupts a PAX3::FOXO1-RUNX2 feed-forward loop and dismantles oncogenic gene programs in fusion-positive rhabdomyosarcoma. (PubMed, bioRxiv) - "RUNX2 inhibition reduces PAX3::FOXO1 expression and signaling, which impairs fusion-positive rhabdomyosarcoma oncogenic phenotypes. In vivo treatment with CADD522 decreased tumor growth and increased survival, indicating that RUNX2 is a promising therapeutic target."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FOXO1 • MYOD1 • PAX3 • RUNX2 • YOD1

HBV activates hepatic stellate cells through RUNX2/ITGBL1 axis. (PubMed, Virol J) - "RUNX2 promotes liver fibrosis in HBV-infected patients by upregulating ITGBL1 expression. Our findings suggest that targeting RUNX2 could be a potential therapeutic approach to mitigate liver fibrosis in chronic hepatitis B."

Journal • Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • RUNX2

In Left Heart Disease, RUNX2/TAZ-Mediated Pulmonary Artery Calcification and Stiffening Promotes Pulmonary Hypertension and Right Ventricular Remodeling (ISHLT 2025) - "The therapeutic potential of RUNX2 or TAZ inhibition by CADD522 or verteporfin was tested in a preclinical model.Results Compared to control samples, PA samples from patients and rats with PH-LHD were characterized by vascular stiffening. Inhibition of either TAZ or RUNX2 attenuated PA calcification, stiffening, and distal artery remodeling, reduced right ventricular systolic pressure, and hypertrophy in AoB rats.Conclusion PH-LHD is associated with PA calcification, which is driven by TAZ-dependent stabilization of RUNX2, leading to osteogenic reprogramming of PASMC. The TAZ/RUNX2 axis may represent a therapeutic target for the treatment of PH-LHD."

Cardiovascular • Heart Failure • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • RUNX2

RUNX2 is stabilised by TAZ and drives pulmonary artery calcification and lung vascular remodelling in pulmonary hypertension due to left heart disease. (PubMed, Eur Respir J) - "Pulmonary hypertension due to left heart disease is associated with pulmonary artery calcification that is driven by TAZ-dependent stabilisation of RUNX2, causing osteogenic reprogramming of pulmonary artery smooth muscle cells. The TAZ-RUNX2 axis may present a therapeutic target in pulmonary hypertension due to left heart disease."

Journal • Cardiovascular • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • RUNX2

ALKBH5-mediated m6A demethylation of Runx2 mRNA promotes extracellular matrix degradation and intervertebral disc degeneration. (PubMed, Cell Biosci) - "Our study elucidates the role of ALKBH5-mediated m6A demethylation of Runx2 mRNA in activating MMPs and ADAMTSs, thereby facilitating ECM degradation and promoting the occurrence of IDD. Our findings suggest that targeting the ALKBH5/Runx2/MMPs/ADAMTSs axis may represent a promising therapeutic strategy for preventing IDD."

Journal • Back Pain • Inflammation • Lumbar Back Pain • Musculoskeletal Pain • Pain • ALKBH5 • RUNX2 • YTHDF1

Runx2 Suppresses Astrocyte Activation and Astroglial Scar Formation After Spinal Cord Injury in Mice. (PubMed, Mol Neurobiol) - "However, these effects were reversed by CADD522...Furthermore, our findings suggest that the Nuclear-matrix-targeting signal (NMTS) of Runx2 is associated with its effect. In summary, the study's results propose that targeting Runx2 may be a promising treatment approach for reactive astrocytes and astroglial scar in the recovery of SCI."

Journal • Preclinical • CNS Disorders • Orthopedics • RUNX2

RUNX2 transcriptional activity is required for CD26high CD4+ T cell development (IMMUNOLOGY 2024) - "Inhibiting RUNX2 DNA binding via small molecule inhibitors CADD522 and DIPQUO resulted significant reduction in development of CD26high CD4 T cells and decreased their cytokine production. These data suggest that RUNX2 may regulate the development and function of CD26high CD4 T cells. Taken together, these results provide evidence for the use of CD26high CD4 T cells in the treatment of solid malignancies with ACT."

Oncology • Solid Tumor • CD4 • DPP4 • IL2RA • RUNX2

YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522. (PubMed, J Bone Oncol) - "In xenograft mouse models, CADD522 as a single agent without surgery significantly reduced tumour volume, increased overall and metastasis-free survival and reduced cancer-induced bone disease. Our results provide insight into PBC molecular abnormalities that have led to the identification of new targets and a new therapeutic."

Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • MIR140 • RUNX2 • YBX1

New bone cancer drug could save children’s lives (ET Healthworld) - "...a new study published in the Journal of Bone Oncology shows how a new drug called 'CADD522' blocks a gene associated with driving cancer's spread, in mice implanted with human bone cancer...The new drug increases survival rates by 50 per cent without the need for surgery or chemotherapy. And unlike chemotherapy, it doesn't cause toxic side effects like hair loss, tiredness and sickness....The team used next-generation sequencing to identify types of genetic regulators called small RNAs that were different during the course of bone cancer progression. They also showed that a gene called RUNX2 is activated in primary bone cancer and that this gene is associated with driving cancer's spread."

Preclinical • Oncology