OICR-9429 / FACIT, Structural Genomics Consortium, Ontario Institute for Cancer Research - LARVOL DELTA

Targeting the compass complex to overcome resistance in KMT2A-rearranged Acute Myeloid Leukemia (ASH 2025) - "Methods To this note, we aimed to establish an in-vitro resistant model in KMT2Ar leukemia cell lines (MV4-11 andMOLM-13) by chronically exposing them to sequentially escalating, sub-therapeutic doses of a menininhibitor (ziftomenib, Selleckchem, cat.no:E1290)...An ATP-based cell proliferation assay was performed to assess cell viabilityand growth inhibition following SiRNA KD and by using WDR5 inhibitor (OICR-9429, Selleckchem,cat.no:S7833) to pharmacologically target the complex...CRISPR knockdowns and patient cells will be tested in xenografts fortherapeutic response.ConclusionASH2L and WDR5 are critical mediators of COMPASS-dependent therapy resistance in KMT2A-r AML.Targeting this complex, particularly ASH2L and WDR5, represents a promising strategy to possibly reverseresistance and improve therapeutic outcomes in resistant KMT2A-r AML. Our preliminary data indicateother components of the COMPASS complex to possibly cause resistance in KMT2A-r AML, and..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • HOXA10 • HOXA9 • KMT2A • MEIS1 • WDR5

Dual Targeting Novel WDR5/ATAD2 Oncogenic Signaling through CK2/Ikaros Axis Demonstrates Synergistic Efficacy in T-ALL (ASH 2023) - "RNA-seq was performed after CEM cells were treated with WDR5 inhibitor (OICR-9429), CX-4945 and vehicle control for 72 hours. Our study reveals a model that dual targeting WDR5/ATAD2 signaling through direct inhibiting oncoproteins and via CK2/IKAROS axis to transcriptionally repress the oncoprotein to achieve synergistic efficacy. Our results further highlight the combination of CX-4945 with WDR5 inhibition is a potential option for the therapy of T-ALL patients."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ATAD2 • IKZF1 • PTPRC • WDR5

Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a. (PubMed, FASEB J) - "Treatment with the MLL1/WDR5 protein-protein interaction inhibitors MM-102 and OICR-9429 reduced H3K4me3 levels and p16INK4a expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO-injected mice...Additionally, we demonstrated that MLL1/WDR5-induced H3K4me3 directly regulates p16INK4a gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing p16INK4a gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis."

Journal • Fibrosis • Hematological Malignancies • Immunology • Inflammation • Leukemia • Oncology • CDKN2A • TGFB1 • WDR5

Investigating the Mechanism of IFN-γ-Inducible Lysosomal Thiol Reductase-Mediated Inhibition of Breast Cancer Cell Proliferation. (PubMed, Cancer Innov) - "This study reveals a potential mechanism by which GILT can slow breast cancer growth, as well as identifying the possible clinical application value of small molecule inhibitor OICR-9429. These data collectively provide novel treatment strategies for breast cancer therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • IFNG • WDR5

New Epigenome Players in the Regulation of PCSK9 - H3K4me3 and H3K9ac Alteration by Statins in hypercholesterolemia. (PubMed, J Lipid Res) - "We observed that atorvastatin increases the fold enrichment of H3K4me3 at the promoter of PCSK9 by elevating the expression of the SET1/COMPASS family of proteins like SET1b and MLL1 in HepG2...Combining statin and OICR-9429 or resveratrol improved the overall uptake of LDL by hepatocytes. Together, these findings suggest that statin induces the colocalization of H3K4me3 and H3K9ac to transcribe PCSK9 actively and that inhibiting these marks reduces PCSK9 expression and ultimately increases hepatocyte LDL uptake. Our study unveils a previously unknown epigenetic mechanism of PCSK9 regulation that may lead to statin resistance or futility in patients and provide a potential therapeutic solution."

Journal • Dyslipidemia • Metabolic Disorders • PCSK9

H3K4me3-Mediated FOXJ2/SLAMF8 Axis Aggravates Thrombosis and Inflammation in β2GPI/Anti-β2GPI-Treated Monocytes. (PubMed, Adv Sci (Weinh)) - "These findings highlight the overexpression of H3K4me3-mediated FOXJ2 in APS, which consequently accelerates APS pathogenesis by triggering inflammation and thrombosis via boosting the SLAMF8/TREM1 axis. Therefore, OICR-9429 is a promising candidate drug for APS therapy."

Journal • Cardiovascular • Genetic Disorders • Hematological Disorders • Inflammation • Thrombosis • SLAMF8 • TLR4

METTL3 orchestrates glycolysis by stabilizing the c-Myc/WDR5 complex in triple-negative breast cancer. (PubMed, Biochim Biophys Acta Mol Cell Res) - "METTL3 binds to the c-Myc/WDR5 complex and promotes glycolysis, which plays a powerful role in promoting TNBC progression. Our findings further broaden our understanding of the role and mechanism of action of METTL3, and may open up new therapeutic avenues for effective treatment of TNBC with high c-Myc expression."

Journal • Breast Cancer • Oncology • Solid Tumor • Transplantation • Triple Negative Breast Cancer • METTL3 • MYC • WDR5

ARID5B-mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti-β2GPI-treated monocytes. (PubMed, Clin Transl Med) - "The H3K4me3 mark and chromatin accessibility at the ARID5B promoter are increased in vitro model mimicked APS. ARID5B-mediated LINC01128 induces pyroptosis and apoptosis via p-STAT3 by binding to BTF3. ARID5B is high- expressed in patients with primary APS and positively correlated with LINC01128 expression. OICR-9429 treatment mitigates pyroptosis and related inflammation in vivo and in vitro models mimicked APS."

Journal • Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Inflammation • Thrombosis • ARID5B • BTF3 • IL1B • LINC01128 • NLRP3 • STAT3

Cooperation of MLL1 and Jun in controlling H3K4me3 on enhancers in colorectal cancer. (PubMed, Genome Biol) - "Taken together, our study illustrates the genome-wide landscape and the regulatory mechanisms of m3Es in CRC, and reveals potential novel strategies for cancer treatment."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CBX8

Cooperative role of the master transcription factor CEBPα during MLL-ENL-mediated leukemic transformation of human CD34+ progenitors (DGHO 2023) - "A combination of the MLL inhibitor MI-503 and OICR-9429 induced strong anti-proliferative effects, superior to single agent treatment. Taken together, our human primary MLL-ENL monocytic AML model allows precise studies about oncogenic mechanisms and drug testing ex vivo . The strong cooperativity of MLL-ENL and CEBPα during leukemic transformation defines CEBPα and its downstream pathways attractive targets to inhibit aggressive human MLL-r leukemia."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CCR2 • CD34 • CEBPA • CXCR4 • FASN • FLT3

Downregulation of BASP1 promotes temozolomide resistance in gliomas via epigenetic activation of the FBXO32/NF-κB/MGMT axis. (PubMed, Mol Cancer Res) - "Importantly, treatment with OICR-9429, an antagonist of the WDR5-MLL interaction, impaired the FBXO32/NF-κB/MGMT axis-mediated repair of TMZ-induced DNA damage, leading to significant apoptosis of BASP1-downregulated glioma cells. These findings shed light on the molecular mechanism underlying BASP1-mediated epigenetic transcriptional repression and may represent a potential strategy in the fight against TMZ-resistant gliomas. Implications: BASP1 downregulation promotes TMZ resistance in gliomas through WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis, providing new target for improving outcomes in patients with TMZ-resistant gliomas."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • Targeted Protein Degradation • FBXO32 • MGMT • NFKBIA • NF-κβ • TRIM37 • WDR5

Inhibition of Wdr5 Attenuates Ang-II-Induced Fibroblast-to-Myofibroblast Transition in Cardiac Fibrosis by Regulating Mdm2/P53/P21 Pathway. (PubMed, Biomolecules) - "For in vivo experiments, we finally proved that the Wdr5 inhibitor OICR9429 significantly reduced Ang-II-induced cardiac fibrosis and increased the expression of P21 in cardiac fibroblasts. Inhibition of Wdr5 may mediate cardiac fibroblast cycle arrest through the Mdm2/P53/P21 pathway and alleviate cardiac fibrosis."

Journal • Fibrosis • Immunology • WDR5

Discovery, evaluation and mechanism study of WDR5-targeted small molecular inhibitors for neuroblastoma. (PubMed, Acta Pharmacol Sin) - "By performing RNA-seq analysis we demonstrated the differences in molecular action mechanisms of the compound 19 and a WIN site inhibitor OICR-9429. Most interestingly, we established the particularly high synergy rate by combining WBM site inhibitor 19 and the WIN site inhibitor OICR-9429, providing a novel therapeutic avenue for neuroblastoma."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • MYCN • WDR5

THERAPEUTIC EFFECT OF TARGETING CASEIN KINASE II / WDR5 AXIS IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2022) - "Conclusion Our data showed that OICR-9429 and CX-4945 have synergistic efficacy in T-ALL. Dual targeting WDR5 and CK2 may be a potential therapeutic approach for T-ALL through the CK2-WDR5-ATAD2 axis."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • IKZF1 • WDR5

Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation. (PubMed, iScience) - "Genetic ablation of Mll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated Setbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation."

Journal • Hematological Malignancies • Oncology • HOXA9 • SETBP1

Recruitment of MLL1 Complex Is Essential for SETBP1 to Induce Myeloid Transformation (ASH 2021) - "We further found that pharmacological inhibition of MLL1 complex using a WDR5 inhibitor OICR-9429 efficiently abrogated SETBP1/SETBP1(D/N)-induced transcriptional activation and transformation. Thus, MLL1 complex plays a critical role in Setbp1 -induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation."

Hematological Malignancies • Leukemia • Oncology • Transplantation • HOXA9 • KIT • LMO2 • MECOM • MEF2C • MEIS1 • SETBP1 • SOX4 • WDR5

Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer. (PubMed, J Exp Clin Cancer Res) - "Our novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • AURKA • BIRC5 • CCNB1 • FOXM1 • IFNG • PD-L1 • PLK1 • XRCC2

WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer. (PubMed, Theranostics) - " These data revealed that targeting WDR5 suppressed proliferation, enhanced apoptosis, chemosensitivity to cisplatin and immunotherapy in PCa. Therefore, our findings provide insight into OICR-9429 is a multi-potency and promising therapy drug, which improves the antitumor effect of cisplatin or immunotherapy in PCa."

IO biomarker • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AURKA • BIRC5 • CCNB1 • E2F1 • IFNG • MYC • PD-L1 • PLK1 • XRCC2

Inhibition of the H3K4 methyltransferase MLL1/WDR5 complex attenuates renal senescence in ischemia reperfusion mice by reduction of p16. (PubMed, Kidney Int) - "MM-102 or OICR-9429, both MLL1/WDR5 protein-protein interaction inhibitors, and small interfering RNA (siRNA) for MLL1 or WDR5 suppressed the expression of p16 in mice with ischemia reperfusion injury, accompanied by downregulation of H3K4me3 expression...Finally, chromatin immunoprecipitation identified the p16 promoter at an H3K4me3 site in renal fibroblasts. Thus, our findings show that H3K4me3 inhibition ameliorates ischemia reperfusion-induced renal senescence along with fibrosis and inflammation."

Journal • Preclinical • Acute Kidney Injury • Fibrosis • Hematological Malignancies • Immunology • Inflammation • Leukemia • Nephrology • Oncology • Renal Disease • Reperfusion Injury

[VIRTUAL] Wdr5 promotes metastasis and chemoresistance in prostate cancer: A novel therapeutic target (EAU-I 2020) - "It is our novel discovery that targeting WDR5 by siRNA or OICR-9429 suppressed proliferation and metastasis, and enhanced apoptosis and chemosensitivity to cisplatin of prostate cancer cells by blocking the WDR5-MLL complex mediating H3K4me3. Therefore, our findings provide insight into OICR-9429 might be a multi-potency and promoting anticancer therapy for prostate cancer."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • MLL

Oxidative stress abrogates the degradation of KMT2D to promote degeneration in nucleus pulposus. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In an ex vivo model, application of OICR-9429 (OICR) also attenuated the degeneration of NP according to the H&E and Safranin-O/Fast Green staining assay, and the protein levels of MMP3, MMP9 and MMP13 were down-regulated, as well. In conclusion, we approved that oxidative stress induced ROS production promote the process of NP degeneration by enhancing KMT2D mediated transcriptional regulation of matrix degeneration related genes during NP degeneration."

Journal • Targeted Protein Degradation • KMT2D • MLL • MLL3 • MMP13 • MMP3 • MMP9