BAY-61-3606 / Bayer - LARVOL DELTA

Deciphering the IKZF1 and MAP4K2 protein interactome in RASMut multiple myeloma reveals a novel regulatory pathway of IKZF1 (ASH 2025) - "IKZF1-TurboID andnuclear TurboID (NLS-TurboID) were stably expressed in RASMut MM.1S cells, treated with MAP4K2inhibitor BAY-61-3606 or CELMoD mezigdomide (positive control), then biotin-labeled...These findings highlight the cell-type-specific interactome of IKZF1and underscore its distinct regulatory roles in MM.Mezigdomide, a cereblon E3 ligase modulatory (CELMoD), induces IKZF1 degradation via high-affinityCRBN binding and serves as control for drug-induced IKZF1 interactome...This study presents the first IKZF1 interactome map in MM using TurboID, coupled with a CRISPR-basedfunctional screen, and suggests new pathways such as NF-κB for IKZF1 degradation. Identification of theMAP4K2-dependent IKZF1 degradation mechanism offers a promising strategy to overcome IMiDresistance."

Hematological Malignancies • Infectious Disease • Multiple Myeloma • Targeted Protein Degradation • BCL6 • CD70 • CRBN • DDB1 • DNMT1 • DUSP1 • FOXO3 • HDAC2 • HIC1 • ICAM1 • IKZF1 • IKZF3 • MAP3K1 • MYC • MYCN • PIAS4 • RB1 • STRBP • TP53

THE SYK INHIBITRO BAY 61-3606 DIHYDROCHLORIDE INDUCES APOPTOSIS OF ACUTE MYELOID LEUKEMIA CELLS BY MODULATING PI3K/AKT?NF/κB PATHWAY (EHA 2025) - "Current SYK inhibitors like Entospletinib, Mivavotinib, and Fostamatinib face limitations due to RAS/RAF/MEK/ERK pathway activation and off-target effects. BAY 61-3606 dihydrochloride significantly inhibits the proliferation of acute myeloid leukemia (AML) cells and induces apoptosis. Mechanistically, BAY 61-3606 dihydrochloride downregulates the expression of anti-apoptotic proteins MCL-1 and BCL-XL, thereby activating the apoptotic pathway in AML cells. Additionally, it inhibits the activation of several key signaling pathways, including P-SYK, PI3K/Akt, ERK, NF/κB, and JAK/STAT."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • MCL1 • SYK

SYK identified by bioinformatics analysis promotes the proliferation of multiple myeloma. (PubMed, Expert Rev Hematol) - "In vivo experiments utilizing MM xenograft models demonstrated that BAY61-3606 administration significantly attenuated tumor growth kinetics (p < 0.05). Our findings establish SYK as a therapeutic target in MM, thereby facilitating the development of innovative treatment strategies."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • SYK

PDPN Activation of CLEC5A in the Peri-necrotic Niche Drives TAM Polarization and TME Immunosuppression in Glioblastoma (SNO 2024) - "Moreover, Bay 61-3606, a selective Syk inhibitor, rescued CLEC5A overexpression-mediated TAM-IM polarization and Syk-JAK-STAT3 activation in THP-1 cells. In vivo, both silencing CLEC5A in TAMs and silencing PDPN in GBM cells, as well as pharmacologically targeting Syk delayed glioma growth, prolonged survival and was associated with diminished immunosuppressive TAMs. Collectively, we found that PDPN-CLEC5A-Syk-JAK-STAT3 signaling causes TAM polarization and enhances TME immunosuppression in GBM and can be targeted to suppress growth."

IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Infectious Disease • Malignant Glioma • Oncology • Solid Tumor • CD163 • CLEC5A • JAK2 • MRC1 • PD-L1 • PDPN • SYK

Identification of BAY61-3606 Derivatives With Improved Activity in Splicing Modulation That Induces Inclusion of Cassette Exons Similar to the Splicing Factor 3B Subunit 1 Mutation. (PubMed, Chem Biol Drug Des) - "Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B-8800. Additionally, a group of serine/arginine-rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities."

Journal • SF3B1

Dual targeting of the RAS-MAPK pathway as a personized medicine approach in RASMut multiple myeloma (IMW 2024) - "After doxycycline-induced MAP4K2 knockdown, cells were treated with various concentrations of MEKi trametinib for five days and then analyzed for proliferation, apoptosis, and cell cycle. Additionally, RASMut H929 cells were treated with a combination of trametinib and different MAP4K2i (TL4-12, NG25 and BAY61-3606), followed by proliferation, apoptosis, and cell cycle assays... Our data lay the foundation for personalized treatment of RASMut MM patients, particularly relevant for patients who have failed immunotherapy. The synergistic treatment approach of targeting MAP4K2 and MEK in RASMut MM warrants further investigation in an in vivo setting to validate our findings and potentially translate them into clinical practice."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL6 • IKZF1 • IRF4 • LY6G6D • MAP2K1 • MYC

Syk inhibitors reduce tau protein phosphorylation and oligomerization. (PubMed, Neurobiol Dis) - "Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors-BAY 61-3606 and R406-on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses...In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD."

Journal • Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • SYK

Temporal dynamics of platelet glycoprotein VI and reactive oxygen species: Insights from fresh and stored platelet concentrates (ICKSH 2024) - "The Syk inhibitor, BAY 61-3606, was used to assess the role of Syk activation in ROS generation...Conclusion : The findings indicate that levels of both receptor and ROS generation decrease in a time-dependent manner, suggesting a regression in the quality of platelets over time. This study contrib- utes valuable insights into the dynamics of platelet function and oxidative stress during storage, emphasizing the importance of time-sensitive considerations in platelet transfusion practices."

SYK

Preclinical analyses reveal spleen tyrosine kinase as regulator of pulmonary vasoconstriction (ERS 2023) - "The effects of Syk inhibition (either with BAY 61-3606 or with BI 1002494) on pulmonary vasoconstriction were assessed in human precision-cut lung slices, in analgosedated ventilated pigs as well as in isolated perfused and ventilated mouse lungs... Syk is required for (hypoxic) pulmonary vasoconstriction, and may serve as a therapeutic target in PAH.; Physiology; Pulmonary function testing; Cell and molecular biology"

Preclinical • Cardiovascular • Hypertension • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • NOS3 • SYK

Bisphenol A-induced autophagy ameliorates human B cell death through Nrf2-mediated regulation of Atg7 and Beclin1 expression by Syk activation. (PubMed, Ecotoxicol Environ Saf) - "BPA-induced autophagy was confirmed by the modification of LC3 puncta formation or autophagy flux turnover with the treatment of hydroxychloroquine(HCQ), NHCl and PI3K inhibitors including 3-methyladenine(3-MA), LY294002 and wortmannin. Bay61-3606, Syk inhibitor, decreased LC3 and the expression of Atg7 and Beclin1, leading to the increase of BPA-induced B cell death. The results suggest that BPA-induced autophagy ameliorates human B cell death through Nrf2-mediated regulation of Atg7 and Beclin1 expression."

Journal • ATG7 • BECN1 • NFE2L2 • SYK