SYK spleen associated tyrosine kinase
ENSG00000165025 · protein coding · Open Targets profile
Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development (PubMed:12387735, PubMed:33782605). Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine- phosphorylated ITAM domains (PubMed:12387735, PubMed:9698567). The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains (PubMed:20154219). The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include DEPTOR, MYO1F, VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK (PubMed:8657103, PubMed:12456653, PubMed:15388330, PubMed:18369315, PubMed:34634301, PubMed:39694035, PubMed:8657103). Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition (PubMed:12456653). Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors (PubMed:12456653, PubMed:18369315). It also phosphorylates and activates PLCG1 and the PKC signaling pathway (PubMed:8657103). It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling (By similarity). In addition to its function downstream of BCR also plays a role in T-cell receptor signaling. Also plays a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade (By similarity). Required for the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3- mediated signaling pathway in basophils (By similarity). Also functions downstream of receptors mediating cell adhesion (PubMed:12387735). Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Also plays a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin (PubMed:20154219). Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (By similarity). Acts as a positive regulator of cGAS-STING signaling by mediating phosphorylation of MYO1F, thereby promoting plasma membrane localization and activation of CGAS (PubMed:39694035). {ECO:0000250|UniProtKB:P48025, ECO:0000269|PubMed:12387735, ECO:0000269|PubMed:12456653, ECO:0000269|PubMed:15123770, ECO:0000269|PubMed:15388330, ECO:0000269|PubMed:18369315, ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:20154219, ECO:0000269|PubMed:33782605, ECO:0000269|PubMed:34634301, ECO:0000269|PubMed:39694035, ECO:0000269|PubMed:8657103, ECO:0000269|PubMed:9535867, ECO:0000269|PubMed:9698567}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Approved Drug, Structure with Ligand, High-Quality Ligand, High-Quality Pocket, Druggable Family
- Antibody
- UniProt loc high conf, GO CC high conf, Human Protein Atlas loc
- PROTAC
- UniProt Ubiquitination, Database Ubiquitination, Half-life Data, Small Molecule Binder
gnomAD loss of function constraint: o/e 0.20576000213623047 (upper bound 0.31251001358032227). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 25 registry trials, updated in the last three years, of the most advanced drugs against SYK (fostamatinib, entospletinib, sovleplenib, cerdulatinib, mivavotinib, R-333, lanraplenib, R-343, gusacitinib, PRT-2607), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Jamie Y HurNational Heart, Lung, and Blood Institute (NHLBI) · 2 of 2 trials Phase 2+
- Alice MimsBeat AML · 1 of 1 trials Phase 2+
- Amy ZhouWashington University School of Medicine · 1 of 1 trials Phase 2+
- Anton PozniakNEAT ID · 1 of 1 trials Phase 2+
- Christopher S. KingInova Schar Heart and Vascular · 1 of 1 trials Phase 2+
- Clement LeongAscend Biopharmaceuticals Ltd · 1 of 1 trials Phase 2+
- Fengkui Zhangoffices director · 1 of 1 trials Phase 2+
- Frederick TamImperial College London · 1 of 1 trials Phase 2+
- Gregory SillerCentral Brisbane Dermatology · 1 of 1 trials Phase 2+
- Nichola CooperImperial College London · 1 of 1 trials Phase 2+
- Renchi Yangoffices director · 1 of 1 trials Phase 2+
- Sean P. CollinsVanderbilt University Medical Center · 1 of 1 trials Phase 2+
- Yoshitaka ShimizuKissei Pharmaceutical Co., Ltd. · 1 of 1 trials Phase 2+
- Andrew LowyUCSD · 0 of 1 trials Phase 2+
- Chenyu LinDuke Health · 0 of 1 trials Phase 2+
Registry trials of fostamatinib, entospletinib, sovleplenib, cerdulatinib, mivavotinib, R-333, lanraplenib, R-343, gusacitinib, PRT-2607 updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 18 of 24 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 1 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
29 trials of drugs against SYK were stopped early; 4 give no reason
Terminated, withdrawn and suspended interventional trials of fostamatinib, entospletinib, sovleplenib, cerdulatinib, mivavotinib, R-333, lanraplenib, R-343, gusacitinib, PRT-2607, R-348, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 29.
- terminated · 2025-12-05 · National Heart, Lung, and Blood Institute (NHLBI) · fostamatinib“Clinical trial was halted prematurely due to low enrollment”
- withdrawn · 2025-11-10 · National Heart, Lung, and Blood Institute (NHLBI) · fostamatinib“No responders in parent protocol 000758; this follow-on protocol not activated and PI leaving NIH”
- withdrawn · 2025-09-16 · Hutchmed · matched by the registry's drug synonyms“Sponsor decision”
- terminated · 2025-06-17 · Gilead Sciences · Entospletinib“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.”
- terminated · 2025-05-02 · NEAT ID Foundation · Fostamatinib“Following a meeting of the DSMB on 20th September 2023, the recommendation was made to the sponsor on 26th September 2023 that the Fostamatinib arm of the trial ceases enrolment and study medication is discontinued immediately.”
- withdrawn · 2025-03-13 · National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) · Gusacitinib“Drug company discontinuing study.”
- terminated · 2024-08-07 · Kronos Bio · Lanraplenib“Sponsor decision”
- terminated · 2024-01-10 · Kronos Bio · Entospletinib“Termination was due to significant challenges associated with study enrollment in a genetic subset of fit participants in the front-line acute myeloid leukemia (AML) setting and other challenges associated with post-COVID impacts.”
- terminated · 2023-12-15 · Washington University School of Medicine · Fostamatinib“Low accrual”
- terminated · 2023-09-18 · Asana BioSciences · matched by the registry's drug synonyms“Phase 2 study results”
- terminated · 2023-04-04 · Calithera Biosciences, Inc · Mivavotinib“Sponsor Decision”
- withdrawn · 2023-02-21 · Portola Pharmaceuticals · Cerdulatinib“Sponsor decision to not initiate the trial”
- suspended · 2023-02-06 · Ascend Biopharmaceuticals Ltd · matched by the registry's drug synonyms“Study did not start. Another protocol is being developed. Recruitment on hold.”
- terminated · 2020-11-19 · Gilead Sciences · Entospletinib MM, Entospletinib SDD“Sponsor's decision to discontinue development of entospletinib.”
- terminated · 2020-09-02 · The Lymphoma Academic Research Organisation · Entospletinib“Stop of drug development”
- terminated · 2020-06-02 · Gilead Sciences · Entospletinib“Study was terminated due to safety measures.”
- terminated · 2020-03-06 · Gilead Sciences · Entospletinib“No signal of efficacy with Entospletinib”
- terminated · 2020-01-02 · Gilead Sciences · EntospletinibNo reason given
- terminated · 2019-11-15 · Gilead Sciences · EntospletinibNo reason given
- terminated · 2019-04-17 · Gilead Sciences · EntospletinibNo reason given
- terminated · 2018-12-26 · Gilead Sciences · matched by the registry's drug synonymsNo reason given
- withdrawn · 2015-10-23 · Rigel Pharmaceuticals · Fostamatinib Disodium tablet 100 mg, Fostamatinib Disodium tablet 150 mg“Study withdrawn prior to enrollment of first subject”
- terminated · 2014-06-25 · AstraZeneca · Fostamatinib, Placebo of Fostamatinib“AZ decision to discontinue fostamatinib development in RA; rights to fostamatinib returned to Rigel Pharmaceuticals.”
- terminated · 2014-06-25 · AstraZeneca · Fostamatinib Disodium (R935788)“AZ decision to discontinue fostamatinib development in RA; rights to fostamatinib returned to Rigel Pharmaceuticals.”
- terminated · 2014-05-06 · AstraZeneca · Fostamatinib and placebo injections, Adalimumab and placebo of fostamatinib, Placebo of fostamatinib, fostamatinib, and placebo injections“AZ decision to discontinue fostamatinib development in RA; rights to fostamatinib returned to Rigel Pharmaceuticals.”
Paediatric incentives and obligations for SYK's drugs
For fostamatinib, entospletinib, sovleplenib, cerdulatinib, mivavotinib, R-333, lanraplenib, R-343, gusacitinib, PRT-2607, R-348: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: yes · SYK is on the list. Membership alone neither requires nor waives a pediatric study.Rule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMEA-001196-PIP03-21 (Fostamatinib, Treatment of autoimmune haemolytic anaemia): W: decision granting a waiver in all age groups for all conditions or indications, 31 Jan 2022; EMEA-002058-PIP01-16-M01 (Entospletinib, Treatment of acute myeloid leukaemia): PM: decision on the application for modification of an agreed PIP, 30 Dec 2022; EMEA-001196-PIP02-17 (Fostamatinib, Treatment of idiopathic thrombocytopenic purpura as a model for immunomodulation): W: decision granting a waiver in all age groups for all conditions or indications, date not given; EMEA-001196-PIP01-11 (Fostamatinib, Treatment of chronic idiopathic arthritis (including rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis and juvenile idiopathic arthritis)): W: decision granting a waiver in all age groups for all conditions or indications, 22 Oct 2012Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
- EU orphan designation: yes · EU/3/17/1922 withdrawn 16 Oct 2017: Treatment of acute myeloid leukaemiaRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA EU/3/17/1922, 2026-11-11
- Authorised in the EU: yes · Tavlesse: authorised since 9 Jan 2020Rule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA EPAR Tavlesse, 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: no · FDA's table lists no pediatric approval of fostamatinib, entospletinib, sovleplenib, cerdulatinib, mivavotinib, r-333, lanraplenib, r-343, gusacitinib, prt-2607, r-348Rule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-11
- Registered studies open to children: no · No interventional study of fostamatinib, entospletinib, sovleplenib, cerdulatinib, mivavotinib, r-333, lanraplenib, r-343, gusacitinib, prt-2607, r-348 includes patients under 18Rule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-11
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 15 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.