Protein / target

Cullin-4A

Encoded byCUL4AQ13619Homo sapiensSwiss-Prot

UniProt: Q13619 Ensembl: ENSG00000139842 HGNC: HGNC:2554 NCBI Gene: 8451

Clinically validated

Therapeutic maturity

Approved medicines

Open Targets target-level

View by indication →

Clinical trials

Small-molecule tractable

Druggability

Approved Drug

Protein at a glance

Biological role

Ubiquitin ligase complex scaffold

Strongest disease association

Multiple Myeloma

Via encoding gene CUL4A · Clinical evidence · score 0.61

Therapeutic position

Established drug target

Small molecules

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins.

View complete UniProt function annotation

Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620, PubMed:30166453, PubMed:33854232, PubMed:33854239). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620). The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1 (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620). The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620). DCX(DET1-COP1) directs ubiquitination of JUN (PubMed:14739464). DCX(DDB2) directs ubiquitination of XPC (PubMed:15811626). DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition (PubMed:16678110, PubMed:17041588, PubMed:24209620). DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of p53/TP53 in response to radiation-induced DNA damage and during DNA replication (PubMed:14578910, PubMed:15448697, PubMed:15548678). DCX(DTL) directs autoubiquitination of DTL (PubMed:23478445). In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip (PubMed:16537899). Is involved in ubiquitination of HOXA9 (PubMed:14609952). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207). The DCX(ERCC8) complex (also named CSA complex) plays a role in transcription-coupled repair (TCR) (PubMed:12732143, PubMed:32355176, PubMed:38316879). A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948). The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3) (PubMed:33854232, PubMed:33854239). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:30166453). With CUL4B, contributes to ribosome biogenesis (PubMed:26711351)

Domains and Gene Ontology detail (38)

Domains & features

Cullin neddylation

Gene Ontology

CCul4-RING E3 ubiquitin ligase complex
CCul4A-RING E3 ubiquitin ligase complex
Ccytoplasm
Cnucleoplasm
Cnucleus
Fubiquitin ligase complex scaffold activity
Fubiquitin protein ligase activity
Fubiquitin protein ligase binding
Pcell population proliferation
Pcellular response to UV
PDNA damage response
Pepigenetic regulation of gene expression

759 aa · 88 kDa · 2 isoforms

Biological roles

Reactome v97

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Cell proliferation & survivalGOCell-cycle regulationGOTranscriptional regulationUniProt · GO · ReactomeImmune signallingGO

View supporting evidence

Cell proliferation & survival

·cell population proliferation
·regulation of cell population proliferation

Cell-cycle regulation

·G1/S transition of mitotic cell cycle
·regulation of cell cycle phase transition

Transcriptional regulation

·Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which…
·epigenetic regulation of gene expression
·Transcription-Coupled Nucleotide Excision Repair (TC-NER)

Immune signalling

·regulation of mitotic cytokinesis
·T cell activation

View underlying pathways (10)

Recognition of DNA damage by PCNA-containing replication complex

DNA Damage Recognition in GG-NER

Formation of Incision Complex in GG-NER

Dual Incision in GG-NER

Formation of TC-NER Pre-Incision Complex

Transcription-Coupled Nucleotide Excision Repair (TC-NER)

Dual incision in TC-NER

Gap-filling DNA repair synthesis and ligation in TC-NER

Neddylation

Negative Regulation of DNA Double Strand Break Response

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Interaction neighbourhood

STRING v12.0

Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.

10 strongest partners — larger node and heavier line mean higher confidence

Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.

Approved medicines with mapped indications

3 medicines · 5 areas

Approved therapies targeting this protein, grouped by what they are approved to treat — the disease-first view of the medicines below. Relationships come from the canonical approved-indication graph (ChEMBL phase-4), the same source as the drug cards.

Immune System Diseases3 medicines

lenalidomide pomalidomide Thalidomide

Multiple Myeloma3 medicines

lenalidomide pomalidomide Thalidomide

Anemia1 medicine

lenalidomide

Lymphoma, Mantle-Cell1 medicine

lenalidomide

Myelodysplastic Syndromes1 medicine

lenalidomide

Approved indications from ChEMBL (phase-4), via the canonical drug→disease graph.

Drugs targeting this protein

How approved and investigational drugs engage this protein — mechanism and action type, direct vs complex targeting, and how broadly each acts across other targets. A drug-first view (the section above groups the approved ones disease-first); direct binders with few recorded targets are listed first.

Thalidomide

ApprovedInhibitor

CRL4(CRBN) E3 ubiquitin ligase inhibitor

Indicated for Immune System Diseases, Multiple Myeloma

Acts on a complex — shared with CRBN, DDB1, RBX1 · 1 of 4 recorded protein targets

lenalidomide

ApprovedInhibitor

CRL4(CRBN) E3 ubiquitin ligase inhibitor

Indicated for Anemia, Immune System Diseases, Lymphoma, Mantle-Cell, Multiple Myeloma

Acts on a complex — shared with CRBN, DDB1, RBX1 · 1 of 4 recorded protein targets

pomalidomide

ApprovedInhibitor

CRL4(CRBN) E3 ubiquitin ligase inhibitor

Indicated for Immune System Diseases, Multiple Myeloma

Acts on a complex — shared with CRBN, DDB1, RBX1 · 1 of 4 recorded protein targets

ChEMBL mechanism, action type, target identity and approved indications. Open Targets clinical status.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene CUL4A

Gene-level evidence surfaced through the gene CUL4A that encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Multiple Myeloma

0.76Well supported

Clinical evidence dominant · Open Targets 0.61

Lymphoma, Mantle-Cell

0.68Moderately supported

Clinical evidence dominant · Open Targets 0.55

Anemia

0.60Moderately supported

Clinical evidence dominant · Open Targets 0.49

Carcinoma, Hepatocellular

0.52Moderately supported

Clinical evidence dominant · Open Targets 0.40

View evidence synthesis (4)

Multiple MyelomaWell supported

0.76

agreement 0.60–0.91

Clinical95%Literature6%

Open Targets aggregate 0.61 · 2 independent evidence families

Lymphoma, Mantle-CellModerately supported

0.68

agreement 0.52–0.83

Clinical100%Literature0%

Open Targets aggregate 0.55 · 2 independent evidence families

AnemiaModerately supported

0.60

agreement 0.45–0.76

Clinical99%Literature1%

Open Targets aggregate 0.49 · 2 independent evidence families

Carcinoma, HepatocellularModerately supported

0.52

agreement 0.37–0.68

Clinical80%Literature20%

Open Targets aggregate 0.40 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations

Multiple Myeloma0.61

Lymphoma, Mantle-Cell0.55

Anemia0.49

Carcinoma, Hepatocellular0.40

Drug development

4 compounds recorded · 3 approved · 1 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 3 drugs that target this protein in Forefront's canonical graph (3 with a mapped approved indication, shown above): these count different sets and are not a subset relation.

View all recorded compounds (4)

IBERDOMIDEPhase 3

POMALIDOMIDEApproval

LENALIDOMIDEApproval

THALIDOMIDEApproval

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small molecules — Strong

Approved Drug and High-Quality Ligand support this modality.

Protein degraders — Emerging

Feasibility evidence (uniprot ubiquitination and database ubiquitination) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (7)

SM · Approved DrugSM · High-Quality LigandSM · High-Quality PocketPR · UniProt UbiquitinationPR · Database UbiquitinationPR · Half-life DataPR · Small Molecule Binder

Raw Open Targets tractability assessment buckets, by modality.

Clinical trials

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein. Ranked by active status, then clinical phase and recency, and spread across the targeting drugs.

Accelerate Improvement in Multiple Myeloma for Newly Diagnosed Transplant-Eligible PatientsPHASE3

NOT_YET_RECRUITING · via lenalidomide · NCT07671287

A Phase 3 Randomized Study Comparing IBI3003 Versus Treatment Per Investigator's Choice in Participants With Relapsed or Refractory Multiple MyelomaPHASE3

NOT_YET_RECRUITING · via pomalidomide · NCT07623798

A Randomized, Open-Label, Multicenter Phase III Clinical Trial to Evaluate the Efficacy and Safety of TQB2934 Injection Versus Investigator-Selected Regimens in Patients With Relapsed/Refractory Multiple MyelomaPHASE3

NOT_YET_RECRUITING · via pomalidomide · NCT07569757

An Open-Label, Randomized Phase 3 Study of Linvoseltamab Monotherapy and Linvoseltamab Plus Carfilzomib Versus Standard of Care Combination Regimens in Patients With Relapsed/Refractory Multiple MyelomaPHASE3

RECRUITING · via pomalidomide · NCT07222761

View all trials (26)

A Phase 3 Randomized, Open-label, Multicenter Study to Evaluate the Safety and Efficacy of SCTC21C in Combination With Bortezomib, Lenalidomide and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Not Eligible for TransplantPHASE3

RECRUITING · via lenalidomide · NCT07297329

A Phase 3, Open-label, Controlled, Randomized Study of Newly Diagnosed Multiple Myeloma Treatment, Designed to Evaluate the Efficacy and Safety of the Elranatamab-lenalidomide Combination as a Replacement for Chemotherapy Followed by Autologous Stem Cell Transplant in the Consolidation Phase, and to Compare Elranatamab With Standard of Care in the Maintenance PhasePHASE3

RECRUITING · via lenalidomide · NCT06918002

A Randomized, Multicenter, Double-Blind, Parallel-Controlled, Phase III Clinical Study to Evaluate QL2109/ DARZALEX FASPRO® in Combination With Pomalidomide and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma Who Have Received at Least One Prior Line of Therapy With Both Lenalidomide and a Proteasome InhibitorPHASE3

NOT_YET_RECRUITING · via pomalidomide · NCT06742138

FeAsiBility of a Treatment Free Interval in Newly Diagnosed mUltiple myeLOma Patients Treated With DaratumUmab-Lenalidomide-DexamethaSone- the FABULOUS Study. A Nationwide Open-label Randomized Phase III Clinical Trial Comparing Daratumumab-lenalidomide-dexamethasone Continuously Versus Including a Treatment Free IntervalPHASE3

RECRUITING · via lenalidomide · NCT06187441

A Phase 3 Randomized Study Comparing Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Ciltacabtagene Autoleucel Versus Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Autologous Stem Cell Transplant (ASCT) in Participants With Newly Diagnosed Multiple Myeloma Who Are Transplant EligiblePHASE3

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT05257083

A Phase 3 Randomized Study Comparing Teclistamab in Combination With Daratumumab SC and Lenalidomide (Tec-DR) and Talquetamab in Combination With Daratumumab SC and Lenalidomide (Tal-DR) Versus Daratumumab SC, Lenalidomide, and Dexamethasone (DRd) in Participants With Newly Diagnosed Multiple Myeloma Who Are Either Ineligible or Not Intended for Autologous Stem Cell Transplant as Initial TherapyPHASE3

RECRUITING · via lenalidomide · NCT05552222

A Phase 3, Open-Label Study to Evaluate Safety and Efficacy of Epcoritamab in Combination With Rituximab and Lenalidomide (R2) Compared to R2 in Subjects With Relapsed or Refractory Follicular Lymphoma (EPCORE FL-1)PHASE3

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT05409066

A Phase III, Multicenter, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin in Combination With Pomalidomide and Dexamethasone (B-Pd) Versus Pomalidomide Plus Bortezomib and Dexamethasone (PVd) in Participants With Relapsed/Refractory Multiple Myeloma (DREAMM 8)PHASE3

ACTIVE_NOT_RECRUITING · via pomalidomide · NCT04484623

A Randomized, Open-label Phase 3 Study of Carfilzomib, Lenalidomide, and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone (KRd vs. VRd) in Patients With Newly Diagnosed Multiple Myeloma (COBRA)PHASE3

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT03729804

A Randomized Phase III Trial Assessing the Benefit of the Addition of Isatuximab to Lenalidomide / Bortezomib / Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple MyelomaPHASE3

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT03617731

Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients With Asymptomatic High-Risk Smoldering Multiple MyelomaPHASE3

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT01169337

A Randomized, Phase III Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib, and Dexamethasone (RVD) to High-Dose Treatment With Peripheral Stem Cell Transplant in the Initial Management of Myeloma in Patients Up to 65 Years of AgePHASE3

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT01208662

A Prospective, Single-Arm, Single-Center, Phase II Study Evaluating the Safety and Efficacy of CM336 in Combination With Isatuximab, Lenalidomide, and Bortezomib in Newly Diagnosed Primary Plasma Cell LeukemiaPHASE2

NOT_YET_RECRUITING · via lenalidomide · NCT07652905

HM2023-43: A Phase 2 Trial of Tafasitamab in Combination With Lenalidomide+Rituximab in Treatment-naive Follicular Lymphoma and Marginal Zone LymphomaPHASE2

RECRUITING · via lenalidomide · NCT06792825

A Multi-center, Open-label, Phase 2 Randomized Study of Elranatamab Plus Lenalidomide Versus Daratumumab Plus Lenalidomide as Post Transplantation Maintenance Therapy in Patients With Newly-diagnosed Myeloma. IFM 2024-06PHASE2

NOT_YET_RECRUITING · via lenalidomide · NCT06931704

A Phase II Trial of Stereotactic Body Radiotherapy (SBRT) With Lenalidomide Maintenance for Solitary PlasmacytomaPHASE2

RECRUITING · via lenalidomide · NCT06863584

A Study of Bortezomib, Pomalidomide, Dexamethasone in Patients with Systemic AL AmyloidosisPHASE2

RECRUITING · via pomalidomide · NCT06342466

Relapsed Follicular Lymphoma Randomised Trial Against Standard ChemoTherapy (REFRACT): A Randomised Phase II Trial of Investigator Choice Standard Therapy Versus Sequential Novel Therapy Experimental ArmsPHASE2

RECRUITING · via lenalidomide · NCT05848765

Combination Post-transplant Consolidation Therapy With Isatuximab, Lenalidomide, Dexamethasone (IsaRD) in Multiple Myeloma Patients With Persistent Marrow Minimal Residual Disease (Elimination of MRD After Transplant; E-MAT)PHASE2

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT05690984

Phase II Study of Belantamab Mafodotin in Combination With Carfilzomib, Pomalidomide, and Dexamethasone (KPd) in Patients With Relapsed Multiple MyelomaPHASE2

RECRUITING · via pomalidomide · NCT05789303

International, Multi-center, Open-label, Treatment Extension Study in Patients With Multiple Myeloma Who Are Still Benefitting From Isatuximab-based Therapy Following Completion of a Phase 1, 2, or 3 Parental StudyPHASE2

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT05669989

An Open-label Phase I/II Trial of Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Systemic Light-Chain AmyloidosisPHASE1/PHASE2

ACTIVE_NOT_RECRUITING · via pomalidomide · NCT05451771

Randomized Phase 2 Study of Daunorubicin and Cytarabine Liposome + Pomalidomide Versus Daunorubicin and Cytarabine Liposome in Newly Diagnosed AML With MDS-Related ChangesPHASE2

ACTIVE_NOT_RECRUITING · via pomalidomide · NCT04802161

Selinexor(ATG-010) Plus Bortezomib, Lenalidomide and Dexamethasone (XVRd) in High Risk Newly Diagnosed Multiple MyelomaPHASE1/PHASE2

RECRUITING · via lenalidomide · NCT05422027

A Phase 1b/2, Open-Label, Multicenter Study to Evaluate the Safety and Pharmacokinetics of a Modified Tafasitamab IV Dosing Regimen Combined With Lenalidomide in Patients With Relapsed or Refractory Diffuse Large B-Cell LymphomaPHASE1/PHASE2

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT05222555

A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)-DREAMM5 - Sub-study 6 - Belantamab Mafodotin, Nirogacestat, Lenalidomide, and Dexamethasone in CombinationPHASE1/PHASE2

ACTIVE_NOT_RECRUITING · via lenalidomide · NCT07150091

ClinicalTrials.gov via the drug-target graph.

What's happening now

Recent therapeutic activity around this target — regulatory actions, clinical trials and safety signals for 2 drugs that target this protein, plus publications where such a drug is a genuine subject. Every item is reached indirectly through the drug, not the protein itself; incidental mentions (a paper that merely measures a drug) and press items are excluded.

Regulatory approval2026-08-31
Approval: POMALIDOMIDE (ANDA210232)
fda · regulatory · fda · via pomalidomide
Regulatory approval2026-08-31
Approval: POMALIDOMIDE (ANDA213234)
fda · regulatory · fda · via pomalidomide
Regulatory approval2026-08-31
Approval: POMALIDOMIDE (ANDA219718)
fda · regulatory · fda · via pomalidomide
Regulatory approval2026-08-31
Approval: POMALIDOMIDE (ANDA220741)
fda · regulatory · fda · via pomalidomide
Trial status changed2026-08-27
A Phase 3, Multicenter, Randomized, Open Label Study of Etentamig Compared With Standard Available Therapies in Subjects With Relapsed or Refractory Multiple Myeloma (3L+ RRMM Monotherapy Study)
Status changed to Active, not recruiting · ClinicalTrials.gov · via pomalidomide
Trial status changed2026-08-19
A Phase 3 Randomized, Open-Label Multicenter Study of Zanubrutinib (BGB-3111) Plus Anti-CD20 Antibodies Versus Lenalidomide Plus Rituximab in Patients With Relapsed/Refractory Follicular or Marginal Zone Lymphoma
Status changed to Active, not recruiting · ClinicalTrials.gov · via lenalidomide
Trial status changed2026-07-30
64407564MMY3009: A Phase 3 Randomized Study Comparing Talquetamab in Combination With Pomalidomide (Tal-P), Talquetamab in Combination With Teclistamab (Tal-Tec), and Investigator's Choice of Either Elotuzumab, Pomalidomide, and Dexamethasone (EPd) or Pom
Status changed to Active, not recruiting · ClinicalTrials.gov · via pomalidomide
Trial results posted2026-07-28
Phase 2 Study With Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma (MM) With Upfront Daratumumab-based Therapy
Results posted · ClinicalTrials.gov · via lenalidomide
New publication2022-03-01
Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection.
Clinical cancer research : an official journal of the American Association for Cancer Research · 2022 · 38 citations · Europe PMC · via pomalidomide
Safety communication2014-12-11
Drug Safety Update: Lenalidomide (Revlimid): risk of serious hepatic adverse drug reactions
mhra · safety · mhra · via lenalidomide
Safety communication2014-12-11
Drug Safety Update: Lenalidomide (Revlimid▼): update on risk of second primary malignancy
mhra · safety · mhra · via lenalidomide
Safety communication2014-12-11
Drug Safety Update: Lenalidomide: risk of thrombosis and thromboembolism
mhra · safety · mhra · via lenalidomide

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.