Oral epithelial cells express Dectin-1 and recognize β-glucan, which activates SYK and induces the expression of antimicrobial peptides and negative regulators of NF-κB, potentially maintaining oral homeostasis.

P2, N=93, Completed, CSPC Ouyi Pharmaceutical Co., Ltd. | Recruiting --> Completed

When the Syk expression was knocked down by its shRNA, the inhibitory effects of ISL on activated macrophages disappeared, indicating that Syk was at least one of key docking-molecules of ISL. Collectively, ISL could alleviate MCD-induced NAFLD in mice involved with the inhibition of macrophage inflammatory activity by the blockade of Syk-induced inflammasome activation.

P1/2, N=24, Terminated, Kronos Bio | Trial completion date: Oct 2024 --> Apr 2024 | Active, not recruiting --> Terminated; Sponsor decision

P1, N=48, Recruiting, Hutchmed | Not yet recruiting --> Recruiting

Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.

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.

Extensive study of structure-activity relationships led to the identification of 1 (NMS-0963), a highly potent Syk inhibitor (IC50 = 3 nM) endowed with high selectivity within a panel of tested kinases and high antiproliferative activity in SYK-dependent BaF3-TEL/SYK cells and in other BCR-dependent hematological tumor cell lines...In in vivo pharmacokinetics studies, 1, displayed good pharmacokinetics properties, with linear exposure with dose and excellent oral bioavailability. These findings suggest that 1 is a promising new Syk inhibitor for treating BCR-dependent hematological cancers.

P1, N=20, Not yet recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial primary completion date: Mar 2024 --> Aug 2024

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.

Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

P1, N=68, Completed, Boehringer Ingelheim | N=20 --> 68

P=N/A, N=16, Terminated, Rigel Pharmaceuticals | N=45 --> 16 | Active, not recruiting --> Terminated; met minimum enrollment goal, however, enrollment was slow due to the pandemic, therefore, the study was terminated

P1, N=48, Not yet recruiting, Hutchmed

P1, N=140, Active, not recruiting, Hutchmed | Recruiting --> Active, not recruiting

NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.

Drug-gene association analysis revealed that both upregulated and downregulated DEGs were associated with fostamatinib...CMap analysis unveiled SA-83851 as a potential candidate to counteract the effects of DEGs, specifically in cells harbouring mutant TP53. Further research, including in vitro and in vivo validations, is warranted to develop drugs targeting BCSCs.

P1, N=60, Not yet recruiting, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

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.

P1, N=30, Not yet recruiting, Stefanie Sarantopoulos, MD, PhD.

P2/3, N=871, Completed, Sean Collins | Active, not recruiting --> Completed

Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

In this study, cervical cancer HeLa cell line was respectively treated with diphenyleneiodonium (DPI), N-Acetylcysteine (NAC) or lentivirus-shRNA- AQP3...In vivo assays confirmed that the excessive HO transport through AQP3 enhanced the infiltration and metastasis of cervical cancer. These results suggest that AQP3 activates HO/Syk/PI3K/Akt signaling axis through regulating NOX4-derived HO transport to contribute to the progression of cervical cancer, and AQP3 may be a potential target for the clinical treatment of advanced cervical cancer.

P1/2, N=24, Active, not recruiting, Kronos Bio | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2 | N=100 --> 24 | Trial primary completion date: Nov 2023 --> May 2024

P3, N=34, Completed, Kissei Pharmaceutical Co., Ltd. | Active, not recruiting --> Completed | N=24 --> 34

The rutin and astragaline components of T. hemsleyanum root extract, by binding to SYK protein, activated the B cell receptor signaling pathway and restored gut microflora diversity to alleviate UC symptoms in mice.

Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophages. Collectively, the increased antitumor activity of CD8 T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.

Enrollment of additional patients to dose cohort(s) previously cleared for safety and tolerability by the DEC will be allowed under specific conditions. The phase 2 component will further evaluate safety, PK, PD, and anti-leukemic activity of the combination at the LANRA RP2D

We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8 T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity.

This article reviews the biological function of SYK, the relationship between SYK and disease, and therapies targeting SYK. In addition, inspired by new technologies such as proteolysis targeting chimeras (PROTACs) and phosphatase recruiting chimeras (PHORCs), we propose the development of new therapeutic approaches for targeting SYK, such as SYK PROTACs and SYK PHORCs, which may overcome deficiencies of existing methods.

P1, N=25, Not yet recruiting, Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation

Inhibition of Syk could provide a novel therapeutic approach for autoimmune diseases and hematologic malignancies. The manuscript describes the preclinical pharmacology characterization of sovleplenib, a novel Syk inhibitor, in enzymatic and cellular assays in vitro and several murine autoimmune disease models in vivo.

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 patients and families for their time and participation.

Corticosteroids are the standard first-line treatment for ITP, while thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib are recommended for later lines; however, these treatments have limited sustained efficacy and may be associated with short- and long-term side effects that impact QoL. Pts with ITP are dissatisfied with current treatment options because of a perceived lack of efficacy, the burden of short- and long-term side effects, and the need for daily, life-long administration. Additionally, some commonly prescribed treatments for ITP are associated with fatigue. Pts and MDs would like new ITP treatments to offer a sustained period of remission or cure, and pts wish to be able to discontinue them without fear of relapse.

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.

Our study provides an evaluation of LOF SYK mutations, demonstrating that it is frequently associated with rapid recurrence following the surgical removal of the primary tumor, with the majority of these patients featuring a nonsense SYK mutation. Additionally, this small cohort of patients demonstrated a high treatment response rate to immunotherapy. These observations may imply that, although LOF SYK mutations are associated with early relapse in melanoma patients, immunotherapy appears to be an effective treatment.

P2, N=40, Recruiting, Iacta Pharmaceuticals | Not yet recruiting --> Recruiting

Our multi-omics analysis offers deeper perspectives on ESCC invasiveness and unveils new phosphorylated hub proteins with their regulatory kinase. This study also suggests that fostamatinib may be a potential agent for treating ESCC.

Finally, reverse transcription-quantitative PCR and western blotting were used to verify the single gene expression in glioma cells. This may provide prognostic value for the treatment of glioma.