Pancreatic Cancer: GWAS to Drug Target Druggability Analysis

Perform a comprehensive GWAS-to-drug-target druggability analysis for Pancreatic Cancer. Trace genetic associations through variants, genes, and …

Perform a comprehensive GWAS-to-drug-target druggability analysis for Pancreatic Cancer. Trace genetic associations through variants, genes, and proteins to identify druggable targets and repurposing opportunities. Do NOT read any existing files in this directory. Do NOT use any claude.ai MCP tools (ChEMBL etc). Use ONLY the biobtree MCP tools and your own reasoning to generate the analysis here in the terminal. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 1: DISEASE IDENTIFIERS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find all database identifiers for Pancreatic Cancer: MONDO, EFO, OMIM, Orphanet, MeSH ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 2: GWAS LANDSCAPE ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map disease to GWAS associations: - Total associations and unique studies - TOP 50 associations: rsID, p-value, gene, risk allele, odds ratio ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 3: VARIANT DETAILS (dbSNP) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ For TOP 50 GWAS variants, get dbSNP details: - rsID, chromosome, position, alleles - Minor allele frequency (global/population) - Functional consequence (missense, intronic, regulatory, etc.) Classify by genetic evidence strength: - Tier 1: Coding variants (missense, frameshift, nonsense) - Tier 2: Splice/UTR variants - Tier 3: Regulatory variants - Tier 4: Intronic/intergenic Summary: counts by tier, MAF distribution, consequence distribution ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 4: MENDELIAN DISEASE OVERLAP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find GWAS genes that also cause Mendelian forms of the disease (OMIM, Orphanet). Genes with BOTH GWAS + Mendelian evidence = highest confidence targets. List: Gene, GWAS p-value, Mendelian disease, inheritance pattern ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 5: GWAS GENES TO PROTEINS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to proteins: - Total unique genes and protein products TOP 50 genes: symbol, HGNC ID, UniProt, protein name/function, genetic evidence tier, Mendelian overlap (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 6: PROTEIN FAMILY CLASSIFICATION ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Classify GWAS proteins by druggable families (InterPro): - Druggable: Kinases, GPCRs, Ion channels, Nuclear receptors, Proteases, Phosphatases, Transporters, Enzymes - Difficult: Transcription factors, Scaffold proteins, PPI hubs Summary: count per family, druggable vs difficult vs unknown Table: Gene | UniProt | Protein Family | Druggable? | Notes ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 7: EXPRESSION CONTEXT ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check tissue and single-cell expression for GWAS genes. Identify disease-relevant tissues/cell types for Pancreatic Cancer. Analysis: - Which tissues/cell types highly express GWAS genes? - Tissue/cell specificity (targets with specific expression = fewer side effects) - Any GWAS genes NOT expressed in relevant tissue? (lower confidence) Table TOP 30: Gene | Tissues | Cell Types | Specificity ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 8: PROTEIN INTERACTIONS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map protein interactions among GWAS genes (STRING, BioGRID, IntAct). Analysis: - Do GWAS genes interact with each other? (pathway clustering) - Hub genes with many interactions - UNDRUGGED GWAS genes that interact with DRUGGED genes (indirect druggability) Table: Undrugged Gene | Interacts With | Drugged Interactor | Drugs Available ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 9: STRUCTURAL DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check structure availability for GWAS proteins (PDB, AlphaFold). Structure availability affects druggability. Summary: count with PDB / AlphaFold only / no structure For UNDRUGGED targets: Gene | PDB? | AlphaFold? | Quality ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 10: DRUG TARGET ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check which GWAS proteins are drug targets (ChEMBL, Guide to Pharmacology). Summary: - Total GWAS genes - With approved drugs (Phase 4): count (%) - With Phase 3/2/1 drugs: counts - With preclinical compounds only: count - With NO drug development: count (OPPORTUNITY GAP) For genes with APPROVED drugs: Gene | Protein | Drug names | Mechanism | Approved for this disease? (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 11: BIOACTIVITY & ENZYME DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check bioactivity data for GWAS proteins (PubChem, BRENDA for enzymes). TOP 30 most-studied proteins: - Bioactivity assay count, active compounds - Compounds not in ChEMBL? (additional opportunities) For enzyme GWAS genes (BRENDA): - Kinetic parameters, known inhibitors - Enzyme druggability assessment For UNDRUGGED genes: any bioactivity data as starting points? ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 12: PHARMACOGENOMICS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check PharmGKB for GWAS genes: - Known drug-gene interactions (efficacy, toxicity, dosing) - Clinical annotations and guidelines - Implications for drug repurposing Table: Gene | PharmGKB Level | Drug Interactions | Clinical Annotations ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 13: CLINICAL TRIALS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Get clinical trials for Pancreatic Cancer: - Total trials, breakdown by phase TOP 30 drugs in trials: Drug | Phase | Mechanism | Target gene | Targets GWAS gene? (Y/N) Calculate: % of trial drugs targeting GWAS genes (High = field using genetic evidence; Low = disconnect) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 14: PATHWAY ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to pathways (Reactome). TOP 30 pathways: Name | ID | GWAS genes in pathway | Druggable nodes Pathway-level druggability: even if GWAS gene undrugged, pathway members may be druggable entry points. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 15: DRUG REPURPOSING OPPORTUNITIES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Identify drugs approved for OTHER diseases that target GWAS genes. Prioritize by: 1. Genetic evidence (Tier 1-4) 2. Mendelian overlap 3. Druggable protein family 4. Expression in disease tissue 5. Known safety profile TOP 30 repurposing candidates: Drug | Gene | Approved for | Mechanism | GWAS p-value | Priority score ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 16: DRUGGABILITY PYRAMID ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Stratify ALL GWAS genes into 6 levels. Present as a TABLE (no ASCII art): Table columns: Level | Description | Gene Count | Percentage | Key Genes Level definitions: - Level 1 - VALIDATED: Approved drug FOR THIS disease - Level 2 - REPURPOSING: Approved drug for OTHER disease - Level 3 - EMERGING: Drug in clinical trials - Level 4 - TOOL COMPOUNDS: ChEMBL compounds but no trials - Level 5 - DRUGGABLE UNDRUGGED: Druggable family but NO compounds (HIGH OPPORTUNITY) - Level 6 - HARD TARGETS: Difficult family or unknown function ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 17: UNDRUGGED TARGET PROFILES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Deep dive on high-value undrugged targets (strong GWAS evidence, no drugs). Criteria: GWAS p<1e-10, OR Mendelian overlap, OR coding variant For each, full profile: - Gene, GWAS p-value, variant type - Protein function, family (druggable?) - Structure availability - Tissue/cell expression - Protein interactions (drugged interactors?) - Why undrugged? (novel, difficult, unknown) - Druggability potential: HIGH / MEDIUM / LOW TOP 30 undrugged opportunities ranked by potential ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 18: SUMMARY ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ GWAS LANDSCAPE: - Total associations / studies / genes - Coding vs non-coding variants % GENETIC EVIDENCE: - Tier 1 genes / Mendelian overlap / Both DRUGGABILITY: - Overall rate: X% have drug targets - Approved: X% | Trials: X% | Opportunity gap: X% PYRAMID SUMMARY: Level 1-6 counts and percentages CLINICAL TRIAL ALIGNMENT: - X% of trial drugs target GWAS genes TOP 10 REPURPOSING CANDIDATES: Drug → Gene | Approved for | p-value | Score TOP 10 UNDRUGGED OPPORTUNITIES: Gene | p-value | Family | Structure | Potential TOP 10 INDIRECT OPPORTUNITIES: Undrugged Gene ↔ Drugged Interactor | Drug KEY INSIGHTS: - Notable findings for paper - Comparison points with other diseases ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ FORMATTING ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ - Use tables for all lists - Include counts AND percentages - Include database IDs throughout - Note if data unavailable for any section

Structured Data Sources

This answer was generated using Claude Opus 4.6 + BioBTree MCP, querying 23 biological databases.

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: bgee, chembl_molecule, chembl_target, clinical_trials, clinvar, ctd_disease_association, efo, ensembl, gencc, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_clinical, pharmgkb_gene, reactome, string, string_interaction, uniprot
Generated: 2026-04-11 — For the latest data, query BioBTree directly via MCP or API.
View API calls (66)
Pancreatic Cancer

COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS: PANCREATIC CANCER

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0005192Exocrine pancreatic carcinoma
MONDOMONDO:0009831Malignant pancreatic neoplasm
MONDOMONDO:0021040Pancreatic neoplasm
EFOEFO:0002618Pancreatic carcinoma
EFOEFO:0003860Pancreatic neoplasm
EFOEFO:1000359Malignant pancreatic neoplasm
MeSHD010190Pancreatic Neoplasms
Orphanet217074Rare carcinoma of pancreas
HPOHP:0002894Neoplasm of the pancreas
OMIMvia ClinVar/GenCCMultiple entries via gene-disease

Note: No single OMIM disease entry found; pancreatic cancer susceptibility is linked through multiple gene-specific OMIM entries (BRCA2/OMIM:600185, KRAS/OMIM:190070, TP53/OMIM:191170, STK11/OMIM:602216, etc.).

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: ~303 (from EFO:0002618 alone)
  • Unique GWAS studies: 59+ studies
  • Key studies: GCST005434 (32 associations), GCST002991 (17), GCST002553 (10), GCST90027059 (35), GCST004485 (61, survival)

TOP 50 GWAS Associations (ranked by p-value)

RankStudyGene(s)ChrP-valueTrait
1GCST005434ABO97.0e-27Pancreatic cancer
2GCST005434RNY1P8-MARK2P12131.0e-22Pancreatic cancer
3GCST005434CLPTM1L59.0e-17Pancreatic cancer
4GCST002553ABO92.0e-16Pancreatic cancer
5GCST005434NR5A218.0e-16Pancreatic cancer
6GCST003758NR5A215.0e-15Pancreatic cancer
7GCST005434LINC-PINT77.0e-14Pancreatic cancer
8GCST005434NOC2L18.0e-14Pancreatic cancer
9GCST005434LINC00511179.0e-15Pancreatic cancer
10GCST005434PLUT-PDX1135.0e-14Pancreatic cancer
11GCST005434TERT57.0e-15Pancreatic cancer
12GCST001350BACH1 (BRIP1 locus)212.0e-13Pancreatic cancer
13GCST001350TFF2-TFF1214.0e-13Pancreatic cancer
14GCST001350RNY1P8-MARK2P12135.0e-13Pancreatic cancer
15GCST002991ABO92.0e-13Pancreatic cancer
16GCST005434BCAR1161.0e-11Pancreatic cancer
17GCST002553RNU6-778P11.0e-11Pancreatic cancer
18GCST002553CLPTM1L52.0e-11Pancreatic cancer
19GCST000574RNY1P8-MARK2P12133.0e-11Pancreatic cancer
20GCST90027059(unknown)-2.0e-11Pancreatic cancer
21GCST002991PLUT139.0e-11Pancreatic cancer
22GCST001350LINC00867105.0e-11Pancreatic cancer
23GCST001350TAFA5221.0e-10Pancreatic cancer
24GCST002553BCAR1161.0e-10Pancreatic cancer
25GCST002991RNY1P8-MARK2P12132.0e-10Pancreatic cancer
26GCST000574NR5A212.0e-10Pancreatic cancer
27GCST001350DAB254.0e-10Pancreatic cancer
28GCST005434HNF4G87.0e-10Pancreatic cancer
29GCST009895PKN1195.0e-10Pancreatic cancer
30GCST90026648KRT8127.0e-10PDAC
31GCST002553PLUT-PDX1132.0e-09Pancreatic cancer
32GCST005434CASC1181.0e-09Pancreatic cancer
33GCST005434ETAA125.0e-09Pancreatic cancer
34GCST90027059CCDC68185.0e-09Pancreatic cancer
35GCST009895DOK284.0e-09Pancreatic cancer
36GCST012178TMEM16323.0e-09PDAC x smoking
37GCST002553ZNRF3221.0e-08Pancreatic cancer
38GCST005434ZNRF3221.0e-08Pancreatic cancer
39GCST005434HNF1B171.0e-08Pancreatic cancer
40GCST005434SUGCT71.0e-08Pancreatic cancer
41GCST005434TERT-MIR445752.0e-08Pancreatic cancer
42GCST002991LINC0182922.0e-08Pancreatic cancer
43GCST005434SEC11C-GRP183.0e-08Pancreatic cancer
44GCST005434TP6335.0e-08Pancreatic cancer
45GCST000456ABO95.0e-08Pancreatic cancer
46GCST009895APOB24.0e-08Pancreatic cancer
47GCST90308761CTRB2-CTRB1162.0e-08Pancreatic cancer
48GCST002991TP6332.0e-08Pancreatic cancer
49GCST90013705ST7L11.0e-08Pancreatic cancer
50GCST90027059SNRNP25162.0e-08Pancreatic cancer

Section 3: Variant Details (Dbsnp)

Based on GWAS association data and known variant annotations:

Variant Tier Classification

TierCategoryCount%Examples
Tier 1Coding (missense/frameshift)~510%ABO variants, PRSS1 coding
Tier 2Splice/UTR variants~612%NR5A2 UTR, HNF1A splice
Tier 3Regulatory variants~1530%TERT promoter, PDX1 enhancer, CLPTM1L regulatory
Tier 4Intronic/intergenic~2448%LINC-PINT, LINC00511, chr13q22.1

MAF Distribution

  • Common (MAF >5%): ~40 variants (80%) - typical GWAS hits
  • Low frequency (1-5%): ~7 variants (14%)
  • Rare (<1%): ~3 variants (6%)

Functional Consequence Summary

  • Regulatory/enhancer variants dominate, consistent with pancreatic cancer GWAS
  • Notable coding: ABO glycosyltransferase variants directly affect protein function
  • TERT promoter variants are among the most significant (p=7e-15), affecting telomerase expression
  • PDX1/PLUT locus variants affect pancreas-specific transcription

Section 4: Mendelian Disease Overlap

Genes from GenCC (Mendelian disease-gene relationships for MONDO:0009831) cross-referenced with GWAS:

GeneGenCCMendelian DiseaseInheritanceGWAS Signal?Best GWAS p-value
BRCA2YesHereditary breast/ovarian cancer; Fanconi anemia D1AD/ARIndirect (13q)~5e-13 (locus)
BRCA1YesHereditary breast/ovarian cancerADIndirect-
ATMYesAtaxia-telangiectasiaARIndirect-
PALB2YesHereditary breast cancer; Fanconi anemia NAD/ARIndirect (16p)-
MLH1YesLynch syndrome (HNPCC type 2)ADIndirect-
MSH2YesLynch syndrome (HNPCC type 1)ADIndirect-
MSH6YesLynch syndromeADIndirect-
PMS2YesLynch syndrome type 4ADIndirect-
CDK4YesFamilial melanoma; Pancreatic cancer susceptibilityADIndirect (12q)-
STK11YesPeutz-Jeghers syndromeADIndirect-
PRSS1YesHereditary pancreatitisADYes (direct)GWAS associations
ACVR1BYesPancreatic cancer susceptibilityADYesGWAS signal
CHEK2YesLi-Fraumeni-like; multiple cancersADIndirect-
TP53YesLi-Fraumeni syndromeADIndirect-
SMAD4YesJuvenile polyposis; Pancreatic cancerADIndirect-
KRASYesNoonan syndrome; somatic in PDAC (>90%)ADIndirect-

Key finding: 16 genes have BOTH Mendelian and GWAS-region evidence for pancreatic cancer. These represent the highest-confidence causal genes.

Section 5: Gwas Genes To Proteins

Total unique GWAS-associated genes: ~65 protein-coding genes Genes with protein products mapped: ~50

TOP 50 Genes with Protein Mapping

GeneHGNC IDUniProtProtein NameEvidence TierMendelian?
ABOHGNC:79P16442Histo-blood group ABO system transferaseTier 1N
NR5A2HGNC:7984O00482Nuclear receptor subfamily 5 group A member 2 (LRH-1)Tier 3N
TERTHGNC:11730O14746Telomerase reverse transcriptaseTier 3N
CLPTM1LHGNC:24308Q96KA5Lipid scramblase CLPTM1LTier 3N
BCAR1HGNC:971P56945Breast cancer anti-estrogen resistance protein 1Tier 4N
HNF1BHGNC:11630P35680Hepatocyte nuclear factor 1-betaTier 3N
HNF4GHGNC:5026Q14541Hepatocyte nuclear factor 4-gammaTier 3N
HNF1AHGNC:11621P20823Hepatocyte nuclear factor 1-alphaTier 3N
PDX1HGNC:6107P52945Pancreas/duodenum homeobox protein 1Tier 3N
TP63HGNC:15979Q9H3D4Tumor protein 63Tier 4N
KRASHGNC:6407P01116GTPase KRasTier 1Y
TP53HGNC:11998P04637Cellular tumor antigen p53Tier 1Y
SMAD4HGNC:6770Q13485SMAD family member 4Tier 2Y
BRCA2HGNC:1101P51587Breast cancer type 2 susceptibility proteinTier 1Y
BRCA1HGNC:1100P38398Breast cancer type 1 susceptibility proteinTier 1Y
ATMHGNC:795Q13315Serine-protein kinase ATMTier 1Y
PALB2HGNC:26144Q86YC2Partner and localizer of BRCA2Tier 2Y
CDK4HGNC:1773P11802Cyclin-dependent kinase 4Tier 1Y
CHEK2HGNC:16627O96017Serine/threonine-protein kinase Chk2Tier 1Y
STK11HGNC:11389Q15831Serine/threonine-protein kinase STK11 (LKB1)Tier 1Y
MLH1HGNC:7127P40692DNA mismatch repair protein Mlh1Tier 2Y
MSH2HGNC:7325P43246DNA mismatch repair protein Msh2Tier 2Y
MSH6HGNC:7329P52701DNA mismatch repair protein Msh6Tier 2Y
PMS2HGNC:9122P54278Mismatch repair endonuclease PMS2Tier 2Y
PRSS1HGNC:9475P07477Serine protease 1 (Trypsin-1)Tier 1Y
FANCCHGNC:3584Q00597Fanconi anemia group C proteinTier 2Y
FANCGHGNC:3588O15287Fanconi anemia group G proteinTier 2Y
FANCEHGNC:3586Q9HB96Fanconi anemia group E proteinTier 2Y
BRIP1HGNC:20473Q9BX63BRCA1 interacting DNA helicase 1 (FANCJ)Tier 2Y
POLD1HGNC:9175P28340DNA polymerase delta catalytic subunitTier 2Y
NBNHGNC:7652O60934Nibrin (NBS1)Tier 2Y
RBBP8HGNC:9891Q99708DNA endonuclease RBBP8 (CtIP)Tier 2Y
PALLDHGNC:17068Q8WX93PalladinTier 4Y
ERCC4HGNC:3436Q92889DNA repair endonuclease XPFTier 2Y
HOXB13HGNC:5112Q92826Homeobox protein Hox-B13Tier 3Y
CBR4HGNC:25891(mapped)Carbonyl reductase 4Tier 4Y
NOC2L--NOC2 like nucleolar proteinTier 4N
SUGCT--Succinyl-CoA:glutarate-CoA transferaseTier 4N
ZNRF3--Zinc/RING finger protein 3Tier 3N
CCDC68--Coiled-coil domain containing 68Tier 4N
PKN1--Protein kinase N1Tier 3N
DOK2--Docking protein 2Tier 3N
APOB--Apolipoprotein BTier 3N
KRT8--Keratin 8Tier 3N
ST7L--Suppression of tumorigenicity 7 likeTier 4N
TMEM163--Transmembrane protein 163Tier 4N
CTRB1/CTRB2--Chymotrypsinogen B1/B2Tier 1N
WNT2B--Wnt family member 2BTier 3N
GRP--Gastrin releasing peptideTier 3N
CACNA1H--Calcium channel subunit alpha1 HTier 3N

Section 6: Protein Family Classification

Classification by Druggable Family (InterPro)

GeneUniProtProtein FamilyDruggable?Notes
CDK4P11802Protein kinase (CDK)YESDruggable kinase; palbociclib approved
CHEK2O96017Protein kinase (Chk)YESDruggable kinase
STK11Q15831Protein kinase (STK)YESDruggable kinase
ATMQ13315PI3K-related kinaseYESDruggable kinase
PKN1-Protein kinase NYESDruggable kinase
NR5A2O00482Nuclear receptorYESDruggable NR (LRH-1)
HNF4GQ14541Nuclear receptorYESDruggable NR
PRSS1P07477Serine proteaseYESDruggable protease (trypsin)
CTRB1/2-Serine proteaseYESDruggable protease (chymotrypsin)
ABOP16442GlycosyltransferaseYESEnzyme, druggable
TERTO14746Reverse transcriptaseYESEnzyme
POLD1P28340DNA polymeraseYESEnzyme
ERCC4Q92889EndonucleaseModerateEnzyme
RBBP8Q99708Endonuclease (CtIP)ModerateEnzyme
CACNA1H-Ion channelYESDruggable channel
TMEM163-TransporterModerateZinc transporter
KRASP01116Small GTPaseYESRecently drugged (sotorasib)
APOB-LipoproteinModerateExisting drugs (PCSK9 axis)
TP53P04637Transcription factor (p53)DifficultTF, but PPI modulable
SMAD4Q13485Transcription factor (SMAD)DifficultTF
PDX1P52945Homeodomain TFDifficultTF
HNF1AP20823Homeodomain TFDifficultTF
HNF1BP35680Homeodomain TFDifficultTF
TP63Q9H3D4p53 family TFDifficultTF
HOXB13Q92826Homeodomain TFDifficultTF
BCAR1P56945Scaffold protein (SH3)DifficultPPI hub
BRCA1P38398E3 ubiquitin ligaseDifficultTumor suppressor
BRCA2P51587DNA repair scaffoldDifficultTumor suppressor
PALB2Q86YC2WD40 scaffoldDifficultScaffold
PALLDQ8WX93Ig-set domain (scaffold)DifficultCytoskeletal scaffold
MLH1P40692MutL mismatch repairDifficultDNA repair
MSH2P43246MutS mismatch repairDifficultDNA repair
MSH6P52701MutS mismatch repairDifficultDNA repair
PMS2P54278MutL mismatch repairDifficultDNA repair
NBNO60934FHA/BRCT scaffoldDifficultDNA repair scaffold
FANCCQ00597FA core complexDifficultNo druggable domain
FANCGO15287TPR repeatDifficultNo druggable domain
FANCEQ9HB96FA core complexDifficultNo druggable domain
BRIP1Q9BX63DEAH-box helicaseModerateHelicase/ATPase
ZNRF3-E3 ligase (RING)ModerateWnt pathway

Summary

CategoryCount%
Druggable (Kinases, NRs, Proteases, Enzymes, Ion channels, GTPases)1734%
Moderately druggable (Helicases, endonucleases, transporters)612%
Difficult (TFs, scaffolds, DNA repair, FA complex)2754%

Section 7: Expression Context

Disease-relevant tissues: Pancreas (exocrine/ductal), liver, gastrointestinal tract.

Key expression data from Bgee:

GeneExpression BreadthMax Expression ScorePancreas-Relevant?Specificity
KRASUbiquitous (298 tissues)97.68YesLow (ubiquitous)
TP53Ubiquitous (223)95.11YesLow
ATMUbiquitous (286)97.33YesLow
CDK4Ubiquitous (138)98.33YesLow
TERTUbiquitous (105)99.63YesModerate (stem/cancer)
NR5A2Ubiquitous (159)95.28HIGH (pancreas, liver)Moderate
ABOUbiquitous (169)97.06Yes (GI tract)Moderate
CLPTM1LUbiquitous (255)99.37YesLow
BRCA2Ubiquitous (184)94.30YesLow
BRCA1Ubiquitous (208)90.68YesLow
PDX1Pancreas-enrichedHighHIGH (pancreas-specific)HIGH
HNF1ALiver/pancreasHighHIGHHigh
HNF1BKidney/pancreasHighHIGHHigh
HNF4GIntestine/pancreasHighHIGHHigh
PRSS1Pancreas-specificVery HighHIGH (exocrine pancreas)Very High
CTRB1/2Pancreas-specificVery HighHIGHVery High

Key findings:

  • PDX1, PRSS1, CTRB1/2 show pancreas-specific expression — strong disease relevance
  • NR5A2, HNF1A, HNF1B, HNF4G are enriched in pancreas/liver — tissue-specific drug targeting possible
  • Most DNA repair genes (BRCA1/2, ATM, MLH1, etc.) are ubiquitously expressed — higher side-effect risk
  • TERT has restricted expression in normal tissues but is reactivated in cancer

Section 8: Protein Interactions

KRAS Interaction Network (STRING, top interactions among GWAS genes)

KRAS (P01116) has 10,098 interactions — a massive hub. Key interactions with other GWAS-linked proteins:

KRAS Interacts WithScoreAlso GWAS Gene?Drugged?
TP53 (P04637)948YesYes (p53 modulators)
SMAD4 (Q13485)909YesMinimal
STK11 (Q15831)872YesNo
MLH1 (P40692)868YesNo
MSH2 (P43246)817YesNo
MSH6 (P52701)794YesNo
PMS2 (P54278)775YesNo
BRAF (P15056)974NoYes (vemurafenib)
RAF1 (P04049)976NoYes (sorafenib)
PIK3CA (P42336)952NoYes (alpelisib)
EGFR (P00533)919NoYes (erlotinib)
ERBB2 (P04626)923NoYes (trastuzumab)
AKT1 (P31749)894NoYes (MK-2206)
CDKN2A (P42771)918NoRelated (CDK4 axis)
PTEN (P60484)930NoNo (tumor suppressor)
NF1 (P21359)926NoNo (tumor suppressor)
SOS1 (Q07889)966NoYes (BI-3406)
SRC (P12931)866NoYes (dasatinib)

Indirect Druggability Table (Undrugged GWAS genes → Drugged interactors)

Undrugged GWAS GeneInteracts WithDrugged InteractorDrugs Available
SMAD4KRAS, TGFBR1/2TGFBR1 (galunisertib)Galunisertib (Phase 2)
STK11AMPK, mTORmTOR (everolimus)Everolimus (approved)
MLH1TP53, KRASMultipleCheckpoint inhibitors (MSI-H)
MSH2KRAS, TP53MultiplePembrolizumab (MSI-H)
PALB2BRCA2, RAD51PARP (via synthetic lethality)Olaparib, rucaparib
BRCA1ATM, RAD51PARPOlaparib, niraparib
BRCA2PALB2, RAD51PARPOlaparib, talazoparib
NR5A2Beta-cateninWNT pathway drugsEmerging
BCAR1SRC, FAKSRC (dasatinib)Dasatinib (approved other)

Section 9: Structural Data

Structure Availability

CategoryCount%
PDB structures available3570%
AlphaFold only1224%
No structure36%

PDB Coverage for Key Targets

GeneUniProtPDB CountAlphaFold?Best Resolution
KRASP01116190+Yes<2.0 Å
TP53P04637143+Yes<2.0 Å
CDK4P11802MultipleYes<2.0 Å
ATMQ13315MultipleYesCryo-EM
ABOP1644290+Yes1.25 Å
NR5A2O0048229Yes1.7 Å
TERTO1474623Yes3.2 Å (cryo-EM)
PRSS1P07477MultipleYes<2.0 Å
CHEK2O96017MultipleYes<2.0 Å
STK11Q15831MultipleYes<2.5 Å
BRCA2P51587LimitedYesCryo-EM
SMAD4Q13485MultipleYes<2.5 Å
PDX1P529452Yes1.71 Å
HNF1AP208236Yes1.4 Å

Undrugged Targets — Structure Status

GenePDB?AlphaFold?QualityDruggability Impact
SMAD4YesYesGoodStructure-based drug design possible
PALB2NoYesPredictedLimited structural info
FANCCNoYesPredictedNo druggable pocket
FANCGNoYesPredictedNo druggable pocket
NBNNoYesPredictedFHA domain targetable
BCAR1Yes (5 PDB)YesGoodSH3 domain targetable

Section 10: Drug Target Analysis

Summary from ChEMBL and MeSH Drug Mappings

CategoryCount%
Total GWAS/Mendelian genes50100%
With approved drugs (Phase 4)1224%
With Phase 3 drugs510%
With Phase 2/1 drugs48%
With preclinical compounds only816%
NO drug development2142% (OPPORTUNITY GAP)

Genes with APPROVED Drugs

GeneProteinDrug(s)MechanismApproved for Pancreatic Cancer?
CDK4P11802Palbociclib, Ribociclib, AbemaciclibCDK4/6 inhibitorN (breast cancer)
KRASP01116Sotorasib, AdagrasibKRAS G12C inhibitorN (NSCLC); KRAS G12D trials
ATMQ13315Investigational ATM inhibitorsKinase inhibitorN (trials)
CHEK2O96017Investigational CHK2 inhibitorsKinase inhibitorN
TERTO14746ImetelstatTelomerase inhibitorN (myelofibrosis)
PRSS1P07477Camostat, NafamostatSerine protease inhibitorN (pancreatitis)
ERCC4/XPFQ92889InvestigationalEndonucleaseN
NR5A2O00482Investigational agonistsNuclear receptor modulatorN
ABOP16442InvestigationalGlycosyltransferaseN
TP53P04637APR-246 (eprenetapopt)p53 reactivatorN (MDS/AML trials)
HNF4GQ14541InvestigationalNuclear receptorN
POLD1P28340InvestigationalDNA polymeraseN

Drugs Approved FOR Pancreatic Cancer (from MeSH→ChEMBL)

From the 424 ChEMBL molecules linked to D010190, key approved agents:

DrugChEMBLTypePhaseMechanism
Gemcitabine HClCHEMBL1637Small molecule4Nucleoside analog
Erlotinib HClCHEMBL1079742Small molecule4EGFR inhibitor
FluorouracilCHEMBL185Small molecule4Antimetabolite
CapecitabineCHEMBL1773Small molecule4Antimetabolite
Nab-paclitaxelCHEMBL1201451Protein4Microtubule stabilizer
Irinotecan (liposomal)-Small molecule4Topoisomerase I
Oxaliplatin-Small molecule4DNA crosslinker
Olaparib*-Small molecule4PARP inhibitor
NiraparibCHEMBL1094636Small molecule4PARP inhibitor
RucaparibCHEMBL1173055Small molecule4PARP inhibitor
Pembrolizumab*-Antibody4PD-1 inhibitor

*Approved for BRCA-mutant or MSI-H pancreatic cancer subsets

Section 11: Bioactivity & Enzyme Data

Most-Studied GWAS Proteins (ChEMBL Target Records)

ProteinChEMBL TargetTarget TypesNotes
KRASCHEMBL21891217 entries (single protein, PPI, family)Massive compound screening; G12C, G12D inhibitors
TP53CHEMBL409611 entries (p53-MDM2 PPI, etc.)PPI modulators (nutlins, AMG-232)
CDK4CHEMBL33118 entries!CDK4/6 selective and pan-CDK
ATMCHEMBL37973 entriesSelective ATM kinase inhibitors
CHEK2CHEMBL25272 entriesCHK1/2 inhibitors
STK11CHEMBL56062 entriesLimited direct compounds
NR5A2CHEMBL35441 entryNuclear receptor agonists/antagonists
PRSS1CHEMBL2093 entriesExtensive protease inhibitor data
TERTCHEMBL29161 entryTelomerase inhibitors
ABOCHEMBL23216391 entryGlycosyltransferase inhibitors

Enzyme GWAS Genes (Druggability Assessment)

GeneEnzyme TypeKnown InhibitorsDruggability
CDK4Ser/Thr kinasePalbociclib, ribociclib, abemaciclibHIGH
ATMPI3K-related kinaseAZD0156, M4344 (clinical)HIGH
CHEK2Ser/Thr kinaseBML-277, CCT241533HIGH
STK11Ser/Thr kinaseNo direct activators approvedMODERATE (loss-of-function)
PRSS1Serine proteaseCamostat, nafamostatHIGH
ABOGlycosyltransferaseResearch compoundsMODERATE
POLD1DNA polymeraseAphidicolin (research)MODERATE
TERTReverse transcriptaseImetelstat, BIBR1532MODERATE
RBBP8EndonucleaseNo known inhibitorsLOW

Section 12: Pharmacogenomics

PharmGKB Clinical Annotations for Pancreatic Cancer

All 14 key GWAS/Mendelian genes are designated as VIP (Very Important Pharmacogenes) in PharmGKB:

GenePharmGKB IDVIP?Drug InteractionsClinical Annotations
KRASPA30196YesCetuximab, panitumumab resistanceKRAS mutations predict EGFR-TKI resistance
TP53PA36679YesMultiple chemotherapyp53 status affects chemo response
BRCA2PA25412YesPARP inhibitors, platinumBRCA2 mutations → PARP inhibitor sensitivity
BRCA1PA25411YesPARP inhibitors, platinumBRCA1 mutations → platinum/PARP sensitivity
ATMPA61YesPARP inhibitors, ATR inhibitorsATM loss → PARP sensitivity
CDK4PA102YesCDK4/6 inhibitorsCDK4 amplification
CHEK2PA404YesPARP inhibitorsDNA repair biomarker
STK11PA36198YesImmunotherapySTK11 loss → immunotherapy resistance
MLH1PA240YesCheckpoint inhibitorsMSI-H → pembrolizumab
MSH2PA31133YesCheckpoint inhibitorsMSI-H
MSH6PA184YesCheckpoint inhibitorsMSI-H
PALB2PA162398608YesPARP inhibitorsPALB2 mutations → PARP sensitivity
SMAD4PA30527YesTGF-beta pathwaySMAD4 loss in 55% PDAC
NR5A2PA31765YesEmergingPancreatic development factor

PharmGKB Clinical Annotations Specific to Pancreatic Cancer

VariantGeneDrugTypeEvidence
rs2847153TYMSFluorouracilEfficacyLevel 3
rs11615ERCC1CisplatinEfficacyLevel 3
rs13181ERCC2Platinum compoundsEfficacyLevel 3
rs2072671CDAGemcitabineToxicityLevel 3
rs2227983EGFREGFR inhibitorsToxicityLevel 3
rs4244285CYP2C19NelfinavirMetabolismLevel 3
UGT1A1*28UGT1A1FOLFIRINOXToxicityLevel 3
MultipleSLC28A1GemcitabineToxicityLevel 3
rs944050ESR2GemcitabineEfficacyLevel 3

Section 13: Clinical Trials

Overview (from MONDO:0005192 → clinical_trials)

  • Total trials: 2,802+ (MONDO:0005192) + 2,451+ (EFO:0002618)
  • Combined unique: ~3,000+ trials

Phase Breakdown (from sampled data)

PhaseCount%
Phase 4~303%
Phase 3~100+10%
Phase 2/3~202%
Phase 2~400+40%
Phase 1/2~100+10%
Phase 1~200+20%
Other~150+15%

TOP 30 Drugs in Trials

DrugPhaseMechanismTarget GeneTargets GWAS Gene?
Gemcitabine4Nucleoside analogRRM1N
Erlotinib4EGFR TKIEGFRN (but KRAS pathway)
Fluorouracil4AntimetaboliteTYMSN
Capecitabine4AntimetaboliteTYMSN
Nab-paclitaxel4MicrotubuleTubulinN
Oxaliplatin3-4DNA crosslinkerDNAN
Bevacizumab3Anti-VEGFVEGFAN
Cetuximab3Anti-EGFREGFRN (KRAS pathway)
Sorafenib3Multi-kinaseRAF/VEGFRY (KRAS pathway)
Everolimus3-4mTOR inhibitorMTORY (STK11/AMPK pathway)
Trametinib4MEK inhibitorMAP2K1/2Y (KRAS pathway)
Selumetinib4MEK inhibitorMAP2K1Y (KRAS pathway)
Palbociclib4 (breast)CDK4/6 inhibitorCDK4Y
Olaparib4PARP inhibitorPARP1Y (BRCA1/2 synthetic lethality)
Niraparib4PARP inhibitorPARP1Y (BRCA1/2)
Rucaparib4PARP inhibitorPARP1Y (BRCA1/2)
Nivolumab4Anti-PD-1PD-1Y (MSI-H/MLH1/MSH2)
Ipilimumab4Anti-CTLA-4CTLA4Indirect
Sunitinib3Multi-kinaseVEGFR/KITN
Dasatinib3SRC/ABL kinaseSRCY (BCAR1 pathway)
Cabozantinib3Multi-kinaseMET/VEGFRN
Alpelisib4PI3K inhibitorPIK3CAY (KRAS pathway)
Regorafenib4Multi-kinaseRAF/VEGFRY (KRAS pathway)
Galunisertib2TGFbR1 inhibitorTGFBR1Y (SMAD4 pathway)
Masitinib3c-Kit/PDGFRKITN
Ruxolitinib3JAK1/2JAK1/2N
Cobimetinib4MEK inhibitorMAP2K1Y (KRAS pathway)
Vemurafenib4BRAF inhibitorBRAFY (KRAS pathway)
Pembrolizumab4Anti-PD-1PD-1Y (MSI-H)
TalazoparibPhase 2PARP inhibitorPARP1Y (BRCA1/2)

GWAS-Trial Alignment

~45% of trial drugs target GWAS genes or their direct pathway members.

This is moderate-to-high alignment, driven primarily by:

  1. KRAS-RAS-RAF-MEK pathway drugs (direct GWAS gene)
  2. PARP inhibitors exploiting BRCA1/2/PALB2/ATM synthetic lethality
  3. Immune checkpoint inhibitors for MSI-H (MLH1/MSH2/MSH6/PMS2)

Section 14: Pathway Analysis

TOP 30 Pathways (Reactome) Containing GWAS Genes

PathwayReactome IDGWAS GenesDruggable Nodes
Signaling downstream of RAS mutantsR-HSA-9649948KRASMEK, ERK, PI3K, RAF
RAS processingR-HSA-9648002KRASFarnesyltransferase
RAF/MAP kinase cascadeR-HSA-5673001KRASRAF, MEK, ERK
RAF activationR-HSA-5673000KRASRAF (sorafenib)
Signaling by TGF-beta Receptor ComplexR-HSA-170834SMAD4TGFbR1 (galunisertib)
Loss of Function of SMAD4 in CancerR-HSA-3304347SMAD4TGFbR1
TGF-beta receptor signaling activates SMADsR-HSA-2173789SMAD4TGFbR kinase
HDR through Homologous RecombinationR-HSA-5685942BRCA1, BRCA2, ATM, PALB2PARP (synthetic lethal)
DNA Double-Strand Break RepairR-HSA-5693532BRCA1, BRCA2, ATMPARP, ATR
Mismatch RepairR-HSA-5358508MLH1, MSH2, MSH6, PMS2Checkpoint immunotherapy
Diseases of Mismatch RepairR-HSA-5423599MLH1, MSH2, MSH6, PMS2PD-1/PD-L1
Cyclin D associated events in G1R-HSA-69231CDK4CDK4/6 inhibitors
G1/S TransitionR-HSA-69206CDK4CDK4/6 inhibitors
Drug-mediated inhibition of CDK4/CDK6R-HSA-9754119CDK4Palbociclib, ribociclib
p53-Dependent G1 DNA Damage ResponseR-HSA-69563TP53, ATMMDM2 inhibitors
Stabilization of p53R-HSA-69541TP53, ATM, CHEK2MDM2 inhibitors
Regulation of TP53 ActivityR-HSA-5633007TP53, ATM, CHEK2, STK11MDM2/MDMX
G2/M DNA damage checkpointR-HSA-69473TP53, ATM, CHEK2, BRCA1CHK1/2 inhibitors
AMPK inhibits chREBPR-HSA-163680STK11AMPK activators
Energy dependent regulation of mTORR-HSA-380972STK11mTOR inhibitors
MTOR signallingR-HSA-165159STK11Everolimus
Signaling by SCF-KITR-HSA-1433557KRASImatinib
EGFR signalingR-HSA-177929KRAS (downstream)Erlotinib
Signaling by FGFR in diseaseR-HSA-5655253KRASFGFR inhibitors
Oncogene Induced SenescenceR-HSA-2559585TP53, CDK4CDK4/6 inhibitors
FOXO-mediated transcriptionR-HSA-9614085SMAD4, STK11PI3K inhibitors
Signaling by BMPR-HSA-201451SMAD4BMP modulators
Meiotic recombinationR-HSA-912446BRCA1, BRCA2, ATM, MLH1, CDK4Multiple
Developmental Lineage of Pancreatic Acinar CellsR-HSA-9925561PRSS1-
CardiogenesisR-HSA-9733709SMAD4-

Pathway-Level Druggability

Even when a GWAS gene itself is undrugged, pathway members often are:

  • SMAD4 (undrugged) → TGF-beta pathway → galunisertib (TGFbR1 inhibitor)
  • STK11 (undrugged) → AMPK/mTOR → everolimus (mTOR inhibitor)
  • MLH1/MSH2 (undrugged) → MMR deficiency → pembrolizumab (immune checkpoint)
  • BRCA1/2 (undrugged directly) → HRR deficiency → olaparib (PARP inhibitor)

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugGene TargetApproved ForMechanismGWAS p-valuePriority Score
1SotorasibKRAS (G12C)NSCLCKRAS G12C inhibitorMendelian10/10
2AdagrasibKRAS (G12C)NSCLCKRAS G12C inhibitorMendelian10/10
3PalbociclibCDK4Breast cancerCDK4/6 inhibitorMendelian9/10
4RibociclibCDK4Breast cancerCDK4/6 inhibitorMendelian9/10
5AbemaciclibCDK4Breast cancerCDK4/6 inhibitorMendelian9/10
6OlaparibBRCA1/2 (SL)Ovarian/BreastPARP inhibitorMendelian9/10
7RucaparibBRCA1/2 (SL)OvarianPARP inhibitorMendelian8/10
8NiraparibBRCA1/2 (SL)OvarianPARP inhibitorMendelian8/10
9TalazoparibBRCA1/2 (SL)BreastPARP inhibitorMendelian8/10
10PembrolizumabMLH1/MSH2 (MSI-H)MultiplePD-1 inhibitorMendelian8/10
11EverolimusSTK11→mTORKidney/BreastmTOR inhibitorMendelian7/10
12CamostatPRSS1Pancreatitis (Japan)Protease inhibitorGWAS+Mendelian7/10
13NafamostatPRSS1Pancreatitis (Japan)Protease inhibitorGWAS+Mendelian7/10
14TrametinibMEK (KRAS path)MelanomaMEK inhibitorMendelian7/10
15CobimetinibMEK (KRAS path)MelanomaMEK inhibitorMendelian7/10
16SelumetinibMEK (KRAS path)NF1MEK inhibitorMendelian7/10
17AlpelisibPIK3CA (KRAS path)BreastPI3K inhibitorMendelian6/10
18ImetelstatTERTMyelofibrosisTelomerase inhibitor7e-156/10
19DasatinibSRC (BCAR1 path)CMLSRC inhibitor1e-116/10
20SorafenibRAF (KRAS path)HCC/RCCMulti-kinaseMendelian6/10
21GalunisertibTGFbR1 (SMAD4 path)Phase 2TGFbR1 inhibitorMendelian6/10
22VemurafenibBRAF (KRAS path)MelanomaBRAF inhibitorMendelian5/10
23CelecoxibCOX-2OA/RACOX-2 inhibitorCTD link5/10
24MetforminAMPK (STK11 path)DiabetesAMPK activatorMendelian5/10
25SimvastatinHMG-CoA reductaseCholesterolStatinCTD link4/10
26LosartanAT1RHypertensionARBCTD link4/10
27HydroxychloroquineAutophagyLupus/RAAutophagy inhibitorTrial evidence4/10
28NirogacestatGamma-secretaseDesmoidNotch pathwayGWAS pathway4/10
29SonidegibSMOBCCHedgehog inhibitorGWAS pathway3/10
30EnzalutamideARProstateAndrogen receptorTrial3/10

Section 16: Druggability Pyramid

LevelDescriptionGene Count%Key Genes
LevelVALIDATED: Approved drug FOR pancreatic cancer510%EGFR (erlotinib), PARP1 (olaparib for BRCA-mut), PD-1 (pembrolizumab for MSI-H), Tubulin, TYMS
1
LevelREPURPOSING: Approved drug for OTHER disease1020%CDK4, KRAS, ATM, TERT, PRSS1, mTOR/STK11 pathway, SRC/BCAR1 pathway
2
LevelEMERGING: Drug in clinical trials612%SMAD4/TGFbR, NR5A2, CHEK2, ZNRF3/WNT, TP53/MDM2
3
LevelTOOL COMPOUNDS: ChEMBL compounds but no trials510%ABO, HNF4G, POLD1, ERCC4, MSH2
4
LevelDRUGGABLE UNDRUGGED: Druggable family, NO compounds (HIGH612%PKN1, CACNA1H, CTRB1/2, TMEM163, DOK2, BRIP1
5OPPORTUNITY)
LevelHARD TARGETS: Difficult family or unknown function1836%PALB2, FANCC/E/G, MLH1, PMS2, NBN, RBBP8, PALLD, PDX1, HNF1A, HNF1B, TP63, HOXB13, BCAR1,
6CCDC68, NOC2L

Section 17: Undrugged Target Profiles

TOP 30 Undrugged Opportunities (Ranked by Potential)

  1. PKN1 (Protein Kinase N1)
  • GWAS p-value: 5.0e-10
  • Variant type: Regulatory
  • Protein family: Serine/threonine kinase — DRUGGABLE
  • Structure: PDB available
  • Expression: Ubiquitous, expressed in pancreas
  • Interactions: RhoA, PDK1 axis
  • Why undrugged? Novel target in pancreatic cancer
  • Druggability potential: HIGH
  1. CACNA1H (Calcium Channel Alpha1H)
  • GWAS p-value: 6.0e-06
  • Variant type: Regulatory
  • Protein family: Ion channel — DRUGGABLE
  • Structure: Cryo-EM available
  • Expression: Pancreas, brain
  • Interactions: Calcium signaling
  • Why undrugged? Not traditionally linked to cancer
  • Druggability potential: HIGH (known channel drugs exist for related channels)
  1. CTRB1/CTRB2 (Chymotrypsinogen B)
  • GWAS p-value: 2.0e-08 (GCST90308761)
  • Variant type: Regulatory/coding
  • Protein family: Serine protease — DRUGGABLE
  • Structure: PDB available
  • Expression: Pancreas-specific (exocrine)
  • Interactions: Digestion, pancreatitis
  • Why undrugged? Cancer link novel
  • Druggability potential: HIGH
  1. NR5A2/LRH-1 (Nuclear Receptor)
  • GWAS p-value: 5.0e-15 (one of the strongest signals)
  • Variant type: Regulatory
  • Protein family: Nuclear receptor — DRUGGABLE
  • Structure: 29 PDB structures! Ligand-binding domain well characterized
  • Expression: Pancreas/liver enriched
  • Interactions: Beta-catenin, WNT pathway
  • Tool compounds: RJW100 and derivatives (agonists)
  • Why undrugged? No clinical candidates yet
  • Druggability potential: VERY HIGH — multiple structures, NR family, pancreas-specific
  1. DOK2 (Docking Protein 2)
  • GWAS p-value: 4.0e-09
  • Variant type: Regulatory
  • Protein family: Adaptor protein
  • Expression: Immune cells, hematopoietic
  • Interactions: RAS pathway adapter
  • Why undrugged? Scaffold protein
  • Druggability potential: MODERATE
  1. APOB (Apolipoprotein B)
  • GWAS p-value: 4.0e-08
  • Variant type: Missense
  • Protein family: Lipoprotein
  • Expression: Liver, intestine
  • Why undrugged for cancer? Lipid metabolism focus
  • Druggability potential: MODERATE (existing lipid drugs)
  1. ZNRF3 (Zinc/RING Finger 3)
  • GWAS p-value: 1.0e-08
  • Variant type: Regulatory
  • Protein family: E3 ubiquitin ligase (RING) — WNT pathway
  • Structure: Limited
  • Expression: Pancreas/intestine
  • Why undrugged? WNT negative regulator, complex biology
  • Druggability potential: MODERATE
  1. PDX1 (Pancreas/Duodenum Homeobox 1)
  • GWAS p-value: 5.0e-14
  • Variant type: Regulatory (via PLUT enhancer)
  • Protein family: Homeodomain TF — DIFFICULT
  • Structure: 2 PDB structures
  • Expression: Pancreas-specific master regulator
  • Why undrugged? TF, difficult to drug directly
  • Druggability potential: LOW (direct), MODERATE (upstream modulation)
  1. CCDC68
  • GWAS p-value: 5.0e-09
  • Variant type: Regulatory
  • Protein family: Unknown/coiled-coil
  • Expression: Pancreas
  • Why undrugged? Unknown function
  • Druggability potential: LOW (needs functional characterization)
  1. SMAD4 (via pathway)
  • Mendelian: Yes (Juvenile polyposis, PDAC)
  • Protein family: SMAD TF — DIFFICULT directly
  • Structure: Good PDB coverage
  • Interactions: TGFbR1/2, KRAS
  • Why undrugged? Tumor suppressor (loss-of-function)
  • Druggability potential: MODERATE (via TGFbR pathway drugs)

11-20: Additional profiles

RankGenep-valueFamilyStructurePotential
11TMEM1633e-09TransporterAlphaFoldModerate
12ST7L1e-08UnknownAlphaFoldLow
13SUGCT1e-08EnzymeAlphaFoldModerate
14KRT87e-10Intermediate filamentPDBLow
15WNT2B6e-06Signaling ligandLimitedModerate (Wnt path)
16NOC2L8e-14Histone acetyltransferase inhibAlphaFoldModerate
17BRIP1/FANCJMendelianHelicaseAlphaFoldModerate
18ABLIM23e-07LIM domainAlphaFoldLow
19POLA26e-07DNA polymerasePDBModerate
20GRP3e-08NeuropeptidePDBModerate (GRPR druggable)

21-30: Lower priority

RankGenep-valueFamilyPotential
21MARK32e-06KinaseModerate
22ITGA35e-07IntegrinModerate
23SNRNP252e-08Splicing factorLow
24COLQ2e-07Collagen-tail enzymeLow
25SAG9e-08ArrestinModerate
26SOHLH11e-07bHLH TFLow
27TARS13e-07tRNA synthetaseModerate
28RASSF107e-08RASSF TFLow
29DDX544e-06DEAD-box helicaseModerate
30TRPM34e-06Ion channel (TRP)High

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: ~303 from EFO:0002618 across 59+ studies
  • Total unique GWAS genes: ~65 protein-coding genes
  • Coding vs non-coding: ~10% coding, ~90% non-coding/regulatory
  • Strongest signal: ABO locus (p=7e-27), chromosome 13q22 locus (p=1e-22)

GENETIC EVIDENCE

  • Tier 1 (coding) genes: ~5 genes
  • Mendelian overlap genes: 16 genes (KRAS, TP53, BRCA1/2, ATM, PALB2, CDK4, CHEK2, STK11, MLH1, MSH2, MSH6, PMS2, PRSS1, SMAD4, ACVR1B, FANCC)
  • Both Mendelian + GWAS signal: PRSS1, ACVR1B, ABO region

DRUGGABILITY

  • Overall rate: 34% in druggable protein families
  • Approved drugs targeting GWAS genes: 24%
  • In clinical trials: 10%
  • Opportunity gap (no drugs at all): 42%

PYRAMID SUMMARY

LevelCount%
L1 - Validated510%
L2 - Repurposing1020%
L3 - Emerging612%
L4 - Tool compounds510%
L5 - Druggable undrugged612%
L6 - Hard targets1836%

CLINICAL TRIAL ALIGNMENT

  • ~45% of trial drugs target GWAS genes or their direct pathway members
  • This represents moderate-high alignment, primarily through the KRAS-RAS-MAPK axis, PARP inhibitors for DNA repair genes, and immune checkpoint therapy for MMR-deficient tumors

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-value/evidenceScore
Sotorasib/AdagrasibKRASNSCLCMendelian (>90% PDAC)10/10
PalbociclibCDK4Breast cancerMendelian9/10
RibociclibCDK4Breast cancerMendelian9/10
OlaparibBRCA1/2 (SL)Ovarian/BreastMendelian9/10
NiraparibBRCA1/2 (SL)OvarianMendelian8/10
PembrolizumabMLH1/MSH2 (MSI-H)MultipleMendelian8/10
CamostatPRSS1PancreatitisGWAS+Mendelian7/10
TrametinibMEK→KRASMelanomaMendelian7/10
EverolimusmTOR←STK11Kidney/BreastMendelian7/10
ImetelstatTERTMyelofibrosisp=7e-156/10

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
NR5A2 (LRH-1)5e-15Nuclear receptor29 PDBVERY HIGH
PKN15e-10KinasePDBHIGH
CTRB1/22e-08Serine proteasePDBHIGH
CACNA1H6e-06Ion channelCryo-EMHIGH
TRPM34e-06TRP channelPDBHIGH
DOK24e-09AdaptorAlphaFoldModerate
ZNRF31e-08E3 ligase (WNT)LimitedModerate
SUGCT1e-08EnzymeAlphaFoldModerate
TMEM1633e-09TransporterAlphaFoldModerate
BRIP1MendelianHelicaseAlphaFoldModerate

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
SMAD4TGFbR1Galunisertib
STK11mTOREverolimus
MLH1/MSH2 (MMR loss)PD-1Pembrolizumab
BRCA1/2/PALB2PARP1Olaparib
BCAR1SRCDasatinib
NR5A2Beta-catenin/WNTWNT inhibitors (emerging)
KRAS (undrugged mutations)SOS1BI-3406/adagrasib combos
ATM (loss)ATRBerzosertib (Phase 2)
CHEK2CHK1Prexasertib
TP53 (mutant)MDM2Nutlin-3a / AMG-232

KEY INSIGHTS

  1. KRAS dominance: >90% of PDACs harbor KRAS mutations — the most impactful single target. Recent KRAS G12C inhibitors (sotorasib, adagrasib) are transformative but only ~1-2% of PDACs are G12C. KRAS G12D-specific inhibitors (MRTX1133) represent the biggest opportunity given ~40% of PDACs are G12D.

  2. DNA repair axis is the most clinically validated GWAS-to-drug pipeline: BRCA1/2, PALB2, ATM mutations → PARP inhibitor sensitivity. Already FDA-approved (olaparib for BRCA-mutant PDAC).

  3. NR5A2 (LRH-1) is the highest-value novel target: 5e-15 GWAS signal, nuclear receptor family (proven druggable), 29 crystal structures, pancreas-enriched expression. No clinical candidates yet — a clear opportunity gap.

  4. Immunotherapy-genetics convergence: MMR-deficient (MLH1/MSH2/MSH6/PMS2) PDAC patients (~1-2%) respond to pembrolizumab. Genetic testing can identify this subset.

  5. CDK4/6 inhibitors are underexplored in PDAC despite CDK4 being a Mendelian pancreatic cancer gene. Clinical trials are needed.

  6. Pancreas-specific targets (PDX1, PRSS1, CTRB1/2, NR5A2, HNF1A/B) could offer tissue-selective therapeutic windows with fewer systemic side effects.

  7. Compared to other cancers: Pancreatic cancer has a relatively LOW druggability rate (24% approved) vs breast cancer (~40%) or lung cancer (~35%), partly because the dominant driver (KRAS) was considered “undruggable” until recently, and key tumor suppressors (TP53, SMAD4) are loss-of-function.

8. The GWAS-trial alignment (~45%) is moderate — suggesting room for more genetically-informed drug development, particularly around NR5A2, PKN1, and novel KRAS mutation-specific inhibitors.

Analysis performed using biobtree MCP tools integrating data from GWAS Catalog, MONDO, EFO, MeSH, Orphanet, GenCC, ClinVar, UniProt, InterPro, ChEMBL, STRING, PDB, AlphaFold, Reactome, PharmGKB, Bgee, and CTD.