entospletinib (GS-9973) / Gilead, Kronos Bio - LARVOL DELTA

Entospletinib alleviates acute liver injury and acute kidney injury by inhibiting ferroptosis. (PubMed, Eur J Pharmacol) - "Mechanistically, Ent reduced lipid peroxidation and suppressed the expression of haeme oxygenase 1 induced by RSL3. Furthermore, Ent alleviated concanavalin A-induced acute liver injury and cisplatin-induced acute kidney injury in vivo. Our findings demonstrate that Ent is an effective ferroptosis inhibitor, both in vivo and in vitro, suggesting its potential therapeutic value in the treatment of ferroptosis-related diseases."

Journal • Acute Kidney Injury • CNS Disorders • Hepatology • Immunology • Liver Failure • Nephrology • Oncology • Renal Disease

Integrative machine learning and structure-based drug repurposing for identifying potent inhibitors of human SYK activity against cancer. (PubMed, Life Sci) - "Despite the investigation of inhibitors of SYK including fostamatinib, entospletinib, cerdulatinib, and TAK-659 for cancer therapy, their lack of specificity and potential off-target effects remain significant concerns...Rifabutin, darunavir, and sildenafil were found as promising SYK inhibitors, showing strong interactions and stable conformations...Our findings underscore the value of computational methods in drug discovery and advocate for further experimental validation of these compounds as SYK-targeted therapies. This study aims to advance the development of more effective and safer treatments for cancers associated with SYK overexpression."

Journal • Oncology • SYK

EFFICACY AND OUTCOMES OF NOVEL THERAPEUTIC AGENTS AS MONOTHERAPY OR IN COMBINATION WITH CONVENTIONAL THERAPY IN ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2025) - "Agents included Guadectiabine 28%, Magrolimab 7% Alvocidib 3%, Enasidenib 23%,, Flotetuzumab 4%, Vadastuximab 9%, Mitoxantrone 9%, Pevonedistat 2%, Entospletinib 3%, Eprenetapopt 20%, Belinostat 0.5%, Onvansertib 3%, Panobinostat 2%, Cediranib Maleate 1%, Nilotinib 2%, Emavusertib 0.5%, and anti-CD45 antibody (DOTA-BC8) 0.5%. The conventional therapies were azacitidine 20% and cytarabine 17%... This study shows the promising efficacy of novel agents in AML and highlights the need for further prospective trials with larger patient populations to better understand the efficacy and safety outcomes of these agents in patients with AML."

Combination therapy • Monotherapy • Retrospective data • Review • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Thrombocytopenia • TP53

OUTCOMES OF RECENT NOVEL THERAPEUTIC AGENTS IN TP53-MUTATED ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME IN THE FRONTLINE SETTING (EHA 2025) - "Newer agents included Eprenetapopt (27%, n=52/194), Magrolimab (50%, n=97/194), and Entospletinib (23%, n=45 /194). All patients were treated concomitantly with either azacitidine (77%, 149/194) or decitabine (23%, 45/194)... This study demonstrated the promising efficacy of novel agents in TP53-mutated AML and MDS in the frontline setting with acceptable toxicity. However, the results are limited because of the small sample size, and large randomized studies are needed to investigate these newer agents in TP53-mutated myeloid neoplasms."

Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • 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

Kronos Bio Enters into Agreement to Be Acquired by Concentra Biosciences for $0.57 in Cash per Share Plus a Contingent Value Right (The Manila Times) - "Kronos Bio, Inc...announced that it has entered into a definitive merger agreement (the 'Merger Agreement') with Concentra Biosciences, LLC ('Concentra'), whereby Concentra will acquire Kronos Bio for $0.57 in cash per share of Kronos Bio common stock ('Kronos Bio Common Stock'), plus one non-tradeable contingent value right ('CVR'), which represents the right to receive: (i) 50% of the net proceeds in the case of a disposition of the Company's product candidates known as KB-9558 and KB-7898 that occurs within 2 years following closing; (ii) 100% of the net proceeds in the case of a disposition of the Company's product candidates known as KB-0742, lanraplenib and entospletinib that occurs prior to closing..."

M&A • Breast Cancer • Graft versus Host Disease • Lupus • Multiple Myeloma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Ovarian Cancer • Prostate Cancer • Rheumatoid Arthritis

Integrated multi-omics analysis and machine learning refine molecular subtypes and clinical outcome for hepatocellular carcinoma. (PubMed, Hereditas) - "Encouragingly, we observed that the high-CMLBS patients may exhibit increased sensitivity to Alpelisib, AZD7762, BMS-536,924, Carmustine, and GDC0810, whereas they may demonstrate reduced sensitivity to Axitinib, AZD6482, AZD8055, Entospletinib, GSK269962A, GSK1904529A, and GSK2606414, suggesting that CMLBS may contribute to the selection of chemotherapeutic agents for HCC patients. Therefore, in-depth examination of data from multi-omics data can provide valuable insights and contribute to the refinement of the molecular classification of HCC. In addition, the CMLBS model demonstrates potential as a screening tool for identifying HCC patients who may derive benefit from immunotherapy, and it possesses practical utility in the clinical management of HCC."

Clinical data • Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Inflammatory signaling pathways play a role in SYK inhibitor resistant AML. (PubMed, Sci Rep) - "Naive AML cells treated with entospletinib showed a strong downregulation of the same gene sets which were upregulated in the resistant state. Our data suggest that inflammatory signaling pathways play a role in entospletinib resistant AML cells."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HOXA9 • MEIS1 • SYK • TNFA

Gene Expression Profiling in Acute Myeloid Leukemia Patient Subgroups With High and Low Sensitivity Toward SYK Inhibitors. (PubMed, Hematol Oncol) - "This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021. Gene set enrichment analysis further highlighted that high-sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low-sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IL6 • SYK • TGFB1

Identification of Prognostic Signatures and Potential New Therapies in NPM1 Mutant Adult Acute Myeloid Leukemia Patients Using Proteomics (ASH 2024) - "Clinical and molecular features were not biased towards any cluster, except for : age, with younger patients in C1 (median=55yo) and older in C2 (median=65yo); white blood cell count and percentage of blasts, both higher in C3; trisomy 8, higher in C4; M1 cases less common and M5 ones more frequent in C1; and more Venetoclax therapy in C2...Of note, SYK inhibitors, such as entospletinib, and EZH2 inhibitors, such as romidepsin, are being evaluated for myeloid malignancies in clinical trials...Protein signatures are independently prognostic in UV/MV analysis, and could triage patients according to treatment. Moreover, new therapeutic targets that could guide additional therapy to improve outcomes were unraveled."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BIRC5 • CASP3 • CD34 • CEBPA • CHEK1 • DNMT3A • FLT3 • IDH1 • KIT • NOTCH1 • NPM1 • SYK • TGM2

Combined Targeting of SYK and BCL-2 in Acute Myeloid Leukaemia and Mechanism Study (ASH 2024) - "Only 60-80% of adult AML patients can achieve complete remission with the first induction chemotherapy, and 50-80% of AML patients ultimately relapse with the "3+7" first-line treatment regimen based on anthracycline and cytarabine (Ara-C), so there is an urgent need to find safer and more effective targeted therapies. There is an urgent need to find safer and more effective targeted therapies.Venetoclax (ABT-199) is an FDA-approved oral selective Bcl-2 inhibitor with limited anti-leukaemia activity as a single agent, and mechanisms of resistance include up-regulation of anti-apoptotic proteins, compensation of multiple metabolic pathways such as OXPHOS glycolysis, and mutations in BCL-2 and BAX.In 2018, the FDA approved the use of Venetoclax in combination with demethylating drugs (azacitidine ( AZA) or low-dose azacitidine AraC (LDAC)) in combination for newly diagnosed AML in older adults aged 75 years and older, and while this combination greatly improves..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BAX • BCL2 • BCL2L1 • MAPK1 • MCL1 • SYK

Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination With Other Targeted Anti-cancer Therapies in Adults With B-cell Malignancies (clinicaltrials.gov) - P1 | N=203 | Terminated | Sponsor: Gilead Sciences | Active, not recruiting ➔ Terminated; The goal of the study was to improve tolerability while maintaining or increasing efficacy. The results of this study showed no efficacy advantage although the combinations were well tolerated.

Combination therapy • Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Oncology

Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination With Other Targeted Anti-cancer Therapies in Adults With B-cell Malignancies (clinicaltrials.gov) - P1 | N=203 | Active, not recruiting | Sponsor: Gilead Sciences | Trial completion date: Dec 2025 ➔ Dec 2024 | Trial primary completion date: Dec 2025 ➔ Dec 2024

Combination therapy • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Oncology

A pathological study on the efficacy of Syk inhibitors in a Candida albicans-induced aortic root vasculitis murine model. (PubMed, Cardiovasc Pathol) - "Candida albicans-induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis."

Journal • Preclinical • Coronary Artery Disease • Inflammation • Vasculitis • SYK

Podocyte SIRPα reduction aggravates lupus nephritis via promoting T cell inflammatory responses. (PubMed, Cell Rep) - "Supporting this, Syk inhibitor GS-9973 prevents podocyte antigen presentation, resulting in a decrease of T cell activation and mitigation of renal disease caused by SIRPα knockdown or deletion. Our findings reveal an immunoregulatory role of SIRPα loss in promoting podocyte antigen presentation to activate specific T cell immune responses in LN."

Journal • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • SIRPA • SYK

SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights. (PubMed, J Transl Med) - "Our study demonstrates that glioma cells can be activated by macrophages via SIRPB1, subsequently reprogramming the TME, suggesting that SIRPB1 could serve as a promising therapeutic target for gliomas."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CCL2 • CXCL8 • IL1R1 • SYK

The ABCB1 and ABCG2 efflux transporters limit brain disposition of the SYK inhibitors entospletinib and lanraplenib. (PubMed, Toxicol Appl Pharmacol) - "This transporter-mediated restriction of brain penetration for both drugs could be almost fully inhibited by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, without signs of acute toxicity. This interaction was, however, unlikely to be mediated through any of the studied transporters or CYP3A. The obtained insights may perhaps help to further improve the safety and efficacy of entospletinib and lanraplenib."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Oncology • Solid Tumor • ABCB1 • ABCG2 • CYP3A4 • SYK

The regulatory roles of Syk in cell death of cutaneous squamous cell carcinoma cells (AAD 2024) - "In addition, R406 or GS9973 could regulate bcl-family protein including Bid cleavage and mcl-1 decrease and also enhance TRAIL-induced cleavage of caspase-3 and PARP1. These findings indicate the synergistic effect of TRAIL and Syk inhibitors on apoptosis induction of SCC12 cells, suggesting the therapeutic potential of such combination for the treatment of skin cancers."

Genetic Disorders • Hematological Malignancies • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • ANXA5 • CASP3 • IL17A • MCL1 • SYK

Exploring the therapeutic potential of Entospletinib, a selective small molecule inhibitor of spleen tyrosine kinase (Syk), for the treatment of retinoblastoma. (EACR-AACR 2024) - "Conclusion Our findings suggest that Entospletinib impedes cell proliferation and triggers apoptosis by downregulating the expression of the NF-κB/p65 protein in retinoblastoma cells. Due to its substantial antitumor efficacy and pharmacological targetability,Entospletinib emerges as a promising and clinically relevant candidate for retinoblastoma treatment"

IO biomarker • Eye Cancer • Oncology • Pediatrics • Retinal Disorders • Retinoblastoma • Solid Tumor • ANXA5 • BAX • BCL2 • CASP3 • SYK • TNFA

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=2000 | Recruiting | Sponsor: Beat AML, LLC | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The Syk inhibitor entospletinib abolishes dermal-epidermal separation in a fully human ex vivo model of bullous pemphigoid. (PubMed, J Invest Dermatol) - "Taken together, entospletinib abrogates dermal-epidermal separation, likely through inhibition of granulocyte responsiveness to deposited immune complexes. Entospletinib or other Syk inhibitors may provide therapeutic benefit in BP."

Journal • Preclinical • Bullous Pemphigoid • Dermatology • Dermatopathology • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Oncology • SYK

Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) (ASH 2023) - "In an orthotopic mouse model of FLT3-mutant AML, tuspetinib exhibited greater antitumor activity than gilteritinib, entospletinib, venetoclax (VEN), and azacitidine (AZA) and combined favorably with VEN and AZA individually. Tuspetinib was well-tolerated and delivered single agent clinical responses across four dose levels among diverse AML genotypes; with a RP2D of 80 mg chosen for future single agent studies. Although early, the VEN/TUS combination has been well tolerated with preliminary objective responses noted."

Clinical • Monotherapy • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • FLT3 • JAK1 • KIT • NPM1 • SYK • TP53

The selective inhibition of the Syk tyrosine kinase ameliorates experimental autoimmune arthritis. (PubMed, Front Immunol) - "Overall, we found that selective Syk inhibition by entospletinib reduced the activity of autoantibody-induced experimental arthritis, which seems to be based mainly on the effect of the inhibitor on neutrophil functions. Our data raise the possibility that entospletinib could be a good drug candidate in the treatment of human autoimmune arthritis."

Journal • Hematological Disorders • Immunology • Inflammation • Inflammatory Arthritis • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Rheumatoid Arthritis • Rheumatology • SYK

Combined Single Cell Flow Cytometry and Imaging Analyses Reveal Immunomodulatory Effects Exerted By Targeted Phospho-SYK Inhibitors with Elevated Sensitivity in NPM1 Mutated AML (ASH 2023) - P1b/2 | "Entospletinib (ENTO) and lanraplenib (LANRA) are inhibitors of spleen tyrosine kinase (SYK); the latter is a next-generation SYK inhibitor and is currently being evaluated in combination with gilteritinib (GILT) in patients with relapsed or refractory FLT3-mutated AML (NCT05028751)...Two different AML patient cohorts were assessed by ex vivo treatment with ENTO, LANRA and combinations of LANRA (trametinib, gilteritinib (GILT), aPD-1) over a range of time points (2h, 4h, 3d and 9d) and readouts for cellular phenotype (e.g., differentiation state, immune cell populations) and functional readouts (pSYK, viability) for each cohort were analyzed by HP-FC and sc-MI and associated with available mutation information (bulk gene and single cell RNA sequencing)...These support studies investigating the use of pSYK inhibitors in combination with other therapies to reduce tumor burden, and as an improved line of treatment for AML. Acknowledgements: We are appreciative of the..."

Immunomodulating • Acute Myelogenous Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • FLT3 • IDH1 • IDH2 • mTOR • MYC • NPM1 • SYK

Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies (ASH 2023) - "To elucidate the mechanistic contribution of NFATC1 in B-cell death induced by fast Ca2+ oscillations, we tested whether genetic deletion of Nfatc1 is sufficient to rescue B-cell death upon fast Ca2+ oscillation induced by 20 mHz intermittent blue light pulses. As expected, while B-ALL cells retaining intact Nfatc1 rapidly decreased cell viability, the cells with Cre-mediated deletion persistently remained in cell culture upon 20 mHz Ca2+ oscillation. In addition to genetic deletion of Nfatc1, we also found that inducible expression of mutant activators of NF-kB signaling were able to rescue B-cells from cell death induced by high-frequency oscillations: Concurrent expression of Card11L232LI, MYD88L265P and IKK2S177E/S181E not only reduced the frequency of autonomous Ca2+ oscillations but also enabled B-cell survival despite delivery of light-pulses and Ca2+ oscillations at a fast 20 mHz frequency."

Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • NFATC1 • PLCG2 • SYK