entospletinib (GS-9973) / Gilead, Ignota Labs - LARVOL DELTA

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

Platelet SYK promotes solid tumor metastasis via TXA2-mediated immunosuppression. (PubMed, J Thromb Haemost) - "Taken together, our results indicate, that SYK in platelets promotes solid tumor metastasis and tumor immunosuppression. Secretion of TXA2 by platelets is SYK-dependent and can be inhibited by SYK-selective inhibitors, which release anti-tumor CD8+ T cells from TXA2-mediated suppression."

Journal • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Disorder • Melanoma • Oncology • Solid Tumor • CD8 • SYK

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P2/3 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | Phase classification: P1/2 ➔ P2/3 | Trial completion date: Dec 2028 ➔ Dec 2032 | Trial primary completion date: Dec 2028 ➔ Dec 2032

Biomarker • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NPM1

METABOLOMIC SIGNATURES IN UNTREATED AML SERUM ASSOCIATED WITH IN VITRO SENSITIVITY TO SYK INHIBITION (EHA 2026) - "In vitro sensitivity to SYK-selective (Entospletinib, RO9021) and dual SYK/FLT3 inhibitors (Fostamatinib, TAK-659) was assessed by thymidine incorporation assay. Serum metabolomics, being both non ‑ invasive and accessible, may offer valuable insights that help inform individualized therapeutic approaches. These findings are hypothesis-generating and require validation in larger, independent cohorts."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • FLT3 • NPM1 • SYK

Spleen Tyrosine Kinase is a druggable therapeutic target in Parkinson’s disease (WPC 2026) - "Using the orally active small molecule Syk inhibitor Entospletinib, we found that once-daily dosing could prevent striatal dopamine depletion and dopaminergic degeneration...Our results uncover Syk as a new druggable therapeutic target elevated in PD patients. Inhibition of Syk in the CNS could be a novel therapeutic strategy for disease modification in PD by targeting inflammasome driven neuropathology and dopaminergic degeneration."

CNS Disorders • Movement Disorders • Parkinson's Disease • IL1B • NLRP3 • SYK

Metabolomics profiling of acute myelogenous leukemia patients to identify systemic differences associated with in vitro sensitivity to SYK inhibitors. (PubMed, Metabolomics) - "This study highlights potential metabolite signatures associated with in vitro SYK-targeted therapy in AML. These findings support future research to identify potential serum biomarkers, guiding personalized SYK inhibition strategies in AML."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • FLT3 • SYK

PHF23-Related Prognostic Signature Modulates Immune Microenvironment and Promotes Tumor Malignancy in Glioma. (PubMed, Int J Mol Sci) - "Our results identify PHF23 as a critical oncogenic driver in glioma and support the PHF23-RPS for risk stratification. Entospletinib may offer a potential immunomodulatory option for high-risk gliomas."

Biomarker • Journal • Tumor mutational burden • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • TMB

SYK-dependent Lipid Handling in Monocyte-derived Macrophages Governs Functional Recovery after Spinal Cord Injury. (PubMed, Brain Res Bull) - "Pharmacological blockade of SYK with intraperitoneal Entospletinib impaired macrophage phagocytosis, triggered intracellular lipid droplet accumulation, and impeded axonal regrowth and functional recovery...Notably, in triggering receptor expressed on myeloid cell 2 (TREM2) knockout mice, Pustulan treatment restored macrophage phagocytic competence and lipid droplet clearance, identifying TREM2-SYK signaling as the critical axis governing post-SCI macrophage function. Our findings establish SYK as a therapeutic target for reprogramming macrophage lipid metabolism and promoting repair following SCI."

Journal • CNS Disorders • Metabolic Disorders • Orthopedics • CX3CR1 • SYK

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | N=2000 ➔ 3000 | Trial completion date: Dec 2026 ➔ Dec 2028 | Trial primary completion date: Dec 2026 ➔ Dec 2028

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

A systematic review of treatments for cutaneous chronic graft-versus-host disease. (PubMed, Actas Dermosifiliogr) - "Seven randomized controlled trials of extracorporeal photopheresis (ECP) with standard therapy, imatinib, entospletinib with prednisone, ruxolitinib, and ibrutinib with prednisone were eligible for inclusion. In conclusion, of all therapeutic agents reviewed, only ruxolitinib demonstrated high-level evidence of a modest efficacy in treating cutaneous cGVHD and should be considered as a line of therapy in addition to current first-line therapy. Further high-level studies are needed to identify alternative therapeutic agents and validate their efficacy profile."

Journal • Review • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Dermatology • Graft versus Host Disease • Immunology • Transplantation

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."

B Cell Lymphoma • 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

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 Malignancies • Leukemia • Oncology • BAX • BCL2 • BCL2L1 • MAPK1 • MCL1 • 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) - P1/2 | "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

Ignota Labs...has announced its acquisition of Kronos’s clinical assets, istisociclib, a CDK9 inhibitor, and entospletinib and lanraplenib, SYK inhibitors. (Businesswire) - "Kronos’ valuation peaked at $3.5 billion after its IPO; however, it failed to progress its assets past Phase 2 trials and subsequently ceased operations. Given the challenges relating to safety and clinical positioning, Ignota Labs saw promise in the clinical portfolio and has acquired Kronos’s clinical IP in full."

Commercial • Hematological Malignancies • Immunology • Solid Tumor

The spleen tyrosine kinase inhibitor entospletinib resolves inflammation to promote repair following acute kidney injury. (PubMed, JCI Insight) - "The resolution of renal inflammation mediated by entospletinib was associated with a reciprocal increase in resident macrophages, reparative gene expression, preserved tubular integrity, and reduced renal fibrosis. The SYK inhibitor entospletinib resolves renal inflammation and promotes repair following AKI."

Journal • Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • CLEC7A • SYK

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