Back to discover

Protein / target

DNA polymerase delta subunit 3

Encoded byPOLD3Q15054Homo sapiensSwiss-Prot
Clinically validated
Therapeutic maturity
5
Approved medicines
Open Targets target-level
View by indication →
30
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

Protein-macromolecule adaptor

Strongest disease association

Leukemia, Myeloid, Acute

Via encoding gene POLD3 · Clinical evidence · score 0.59

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

Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex.

View complete UniProt function annotation

Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex (PubMed:17317665, PubMed:22801543, PubMed:24449906). As a component of the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3 and Pol-delta4, respectively), plays a role in high fidelity genome replication, including in lagging strand synthesis, and repair. Required for optimal Pol-delta activity. Stabilizes the Pol-delta complex and plays a major role in Pol-delta stimulation by PCNA (PubMed:10219083, PubMed:10852724, PubMed:11595739, PubMed:16510448, PubMed:24035200). Pol-delta3 and Pol-delta4 are characterized by the absence or the presence of POLD4. They exhibit differences in catalytic activity. Most notably, Pol-delta3 shows higher proofreading activity than Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. In this context, POLD3, along with PCNA and RFC1-replication factor C complex, is required to recruit POLD1, the catalytic subunit of the polymerase delta complex, to DNA damage sites (PubMed:20227374). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites performed by Pol-delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH). Facilitates abasic site bypass by DNA polymerase delta by promoting extension from the nucleotide inserted opposite the lesion (PubMed:19074196, PubMed:25628356, PubMed:27185888). Also involved in TLS, as a component of the tetrameric DNA polymerase zeta complex. Along with POLD2, dramatically increases the efficiency and processivity of DNA synthesis of the DNA polymerase zeta complex compared to the minimal zeta complex, consisting of only REV3L and REV7 (PubMed:24449906)

Subcellular location

CytoplasmNucleus
Domains and Gene Ontology detail (13)

Gene Ontology

  • Ccytoplasm
  • Cdelta DNA polymerase complex
  • Cnucleoplasm
  • Czeta DNA polymerase complex
  • Fprotein-macromolecule adaptor activity
  • PDNA biosynthetic process
  • PDNA strand elongation involved in DNA replication
  • PDNA synthesis involved in DNA repair
  • PDNA synthesis involved in UV-damage excision repair
  • PDNA-templated DNA replication
  • Perror-prone translesion synthesis
  • Pmismatch repair

466 aa · 51 kDa · 3 isoforms

Approved medicines with mapped indications

2 medicines · 6 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.

Precursor Cell Lymphoblastic Leukemia-Lymphoma2 medicines
Leukemia, Lymphoid1 medicine
Leukemia, Myeloid, Acute1 medicine
Meningeal Carcinomatosis1 medicine
Meningeal Neoplasms1 medicine
Broader indication categories (1)
Neoplasms2 medicines

Broad umbrella indications (e.g. “Neoplasms”). Shown here because every medicine also appears under a more specific disease above — kept for completeness, de-emphasised for clarity.

5 medicines meet Open Targets' target-level approved-medicine definition; the 2 shown here are those on this page with a canonical approved disease indication in the graph. Approved indications from ChEMBL (phase-4), via the canonical drug→disease graph.

Drugs targeting this protein

2

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.

clofarabine
ApprovedInhibitor

DNA polymerase (alpha/delta/epsilon) inhibitor

Indicated for Precursor Cell Lymphoblastic Leukemia-Lymphoma, Neoplasms

Acts on a complex — shared with POLA1, POLD4, POLD1 +7 more · 1 of 14 recorded protein targets — broad pharmacology

cytarabine
ApprovedInhibitor

DNA polymerase (alpha/delta/epsilon) inhibitor

Indicated for Leukemia, Lymphoid, Leukemia, Myeloid, Acute, Meningeal Carcinomatosis, Meningeal Neoplasms

Acts on a complex — shared with POLA1, POLD4, POLD1 +7 more · 1 of 11 recorded protein targets — broad pharmacology

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 POLD3

Gene-level evidence surfaced through the gene POLD3that 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.

Leukemia, Myeloid, Acute
0.73Moderately supported

Clinical evidence dominant · Open Targets 0.59

Ovarian carcinoma
0.70Moderately supported

Clinical evidence dominant · Open Targets 0.56

Neoplasms
0.68Moderately supported

Clinical evidence dominant · Open Targets 0.55

Myelodysplastic syndrome
0.65Moderately supported

Clinical evidence dominant · Open Targets 0.52

View evidence synthesis (4)
Leukemia, Myeloid, AcuteModerately supported
0.73
agreement 0.560.89
Clinical100%

Open Targets aggregate 0.59 · 1 independent evidence family

Ovarian carcinomaModerately supported
0.70
agreement 0.540.85
Clinical100%Literature0%

Open Targets aggregate 0.56 · 2 independent evidence families

NeoplasmsModerately supported
0.68
agreement 0.520.83
Clinical93%Literature8%

Open Targets aggregate 0.55 · 2 independent evidence families

Myelodysplastic syndromeModerately supported
0.65
agreement 0.490.80
Clinical100%Literature0%

Open Targets aggregate 0.52 · 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
Leukemia, Myeloid, Acute0.59
Ovarian carcinoma0.56
Neoplasms0.55
Myelodysplastic syndrome0.52

Drug development

7 compounds recorded · 5 approved · 2 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 2 drugs that target this protein in Forefront's canonical graph (2 with a mapped approved indication, shown above): these count different sets and are not a subset relation.

View all recorded compounds (7)
CLOFARABINEApproval
GEMCITABINE HYDROCHLORIDEApproval
TROXACITABINEPhase 2
GEMCITABINEApproval
ASPACYTARABINEPhase 2
FLUDARABINE PHOSPHATEApproval
CYTARABINEApproval

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 moleculesStrong

Approved Drug and Structure with Ligand support this modality.

Protein degradersEmerging

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

View underlying tractability evidence (5)
SM · Approved DrugSM · Structure with LigandPR · UniProt UbiquitinationPR · Database UbiquitinationPR · Half-life Data

Raw Open Targets tractability assessment buckets, by modality.

Clinical trials

30

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.

View all trials (26)

ACTIVE_NOT_RECRUITING · via cytarabine · NCT03020030

ClinicalTrials.gov via the drug-target graph.

What's happening now

12

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.

  1. Label change2026-08-03

    Label change: CYTARABINE (ANDA072168)

    fda · regulatory · fda · via cytarabine

  2. Label change2026-08-03

    Label change: CYTARABINE (ANDA072945)

    fda · regulatory · fda · via cytarabine

  3. Label change2026-08-03

    Label change: CYTARABINE (ANDA075383)

    fda · regulatory · fda · via cytarabine

  4. Label change2026-07-29

    Label change: CYTARABINE (ANDA071868)

    fda · regulatory · fda · via cytarabine

  5. Withdrawn from market2023-10-18

    Market withdrawal: Ivozall (EMA)

    ema · market · ema · via clofarabine

  6. New publication2013-02-10
    Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML).

    Investigational new drugs · 2013 · 42 citations · Europe PMC · via cytarabine

  7. New publication2012-05-14
    Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial.

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2012 · 133 citations · Europe PMC · via cytarabine

  8. New publication2009-12-21
    Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors.

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2010 · 151 citations · Europe PMC · via clofarabine

  9. New publication2009-03-01
    Phase II study of intermediate-dose cytarabine in patients with relapsed or refractory Ewing sarcoma: a report from the Children's Oncology Group.

    Pediatric blood & cancer · 2009 · 51 citations · Europe PMC · via cytarabine

  10. Regulatory approval1994-02-28

    Approval: CYTARABINE (ANDA072945)

    fda · regulatory · fda · via cytarabine

  11. Regulatory approval1990-08-31

    Approval: CYTARABINE (ANDA072168)

    fda · regulatory · fda · via cytarabine

  12. Regulatory approval1990-06-04

    Approval: CYTARABINE (ANDA071868)

    fda · regulatory · fda · via cytarabine

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.