Perform a comprehensive GWAS-to-drug-target druggability analysis for
Prostate 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 Prostate 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 Prostate 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 Prostate 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

Question

Perform a comprehensive GWAS-to-drug-target druggability analysis for
Prostate 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 Prostate 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 Prostate 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 Prostate 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

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
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

Accepted Answer

COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS: PROSTATE CANCER
Section 1: Disease Identifiers
DatabaseIdentifierName MONDOMONDO:0008315Prostate cancer (hereditary/familial) MONDOMONDO:0005159Prostate carcinoma MONDOMONDO:0021259Prostate neoplasm EFOEFO:0001663Prostate carcinoma MeSHD011471Prostatic Neoplasms HPOHP:0012125Prostate cancer HPOHP:0100787Prostate neoplasm OMIMVia HGNC:5112 (HOXB13) → MIM linkHereditary prostate cancer (HPC1-like) Cross-references from MONDO:0008315 …

Cross-references from MONDO:0008315	Cross-references from EFO:0001663
1,139 GWAS associations, 5,767 clinical trials, 1,063 ClinVar entries, 14 GenCC curated gene-disease links, 28 GWAS studies.
	2,978 GWAS associations, 120 GWAS studies, 113 ChEMBL molecules, 4,832 clinical trials.

#	GWAS ID	rsID/Locus	Gene(s)	Chr	p-value	Study Trait
1	GCST90428117_202	8q24	PCAT1	8	2e-44	Prostate cancer
2	GCST90428117_203	8q24	PCAT1, CASC8, POU5F1B, CCAT2	8	1e-43	Prostate cancer
3	GCST90399469_4	8q24	CASC8 - CASC11	8	9e-43	Prostate cancer
4	GCST90399469_5	8q24	PCAT1, CASC19, PRNCR1	8	4e-42	Prostate cancer
5	GCST90428117_204	8q24	PCAT1, CASC19	8	4e-40	Prostate cancer
6	GCST90428117_205	17q21	HOXB13	17	1e-38	Prostate cancer
7	GCST90428117_206	8q24	CASC19, PCAT1	8	1e-37	Prostate cancer
8	GCST90428117_207	17q12	HNF1B	17	5e-35	Prostate cancer
9	GCST90428117_208	17q12	HNF1B	17	4e-34	Prostate cancer
10	GCST001719_1	8q24	PCAT1, CASC19	8	6e-34	Prostate cancer
11	GCST90043894_1	8q24	PCAT1, CASC19	8	3e-34	ICD10 C61
12	GCST90428117_209	8q24	CASC8 - CASC11	8	1e-32	Prostate cancer
13	GCST90428117_210	10q11	MSMB	10	1e-32	Prostate cancer
14	GCST90428117_211	17q21	ATP5MC1 - UBE2Z	17	5e-32	Prostate cancer
15	GCST90428117_27	11q13	SMIM38 - MYEOV	11	3e-31	Prostate cancer
16	GCST000488_10	8p21	NKX3-1	8	3e-30	Prostate cancer
17	GCST000488_12	22q13	BIK	22	6e-29	Prostate cancer
18	GCST90428117_28	19q13	KLK3	19	3e-29	Prostate cancer
19	GCST000152_2	10q11	MSMB	10	9e-29	Prostate cancer
20	GCST002890_4	17q12	HNF1B	17	8e-29	Prostate cancer
21	GCST90043894_2	17q21	HOXB13	17	2e-29	ICD10 C61
22	GCST000750_1	8q24	CASC8 - CASC11	8	1e-25	Prostate cancer
23	GCST90042670_1	8q24	PCAT1, CASC19	8	8e-25	Father: Prostate cancer
24	GCST001148_2	5p15	TERT	5	3e-24	Prostate cancer
25	GCST90428117_29	11q13	MIR4686 - ASCL2	11	3e-24	Prostate cancer
26	GCST000488_2	2q31	ITGA6	2	9e-23	Prostate cancer
27	GCST90428117_30	6q25	SLC22A1 - SLC22A2	6	1e-22	Prostate cancer
28	GCST90399469_6	8q24	PCAT1, CASC19	8	9e-21	Prostate cancer
29	GCST90428117_31	8q24	CASC8, PCAT1, POU5F1B	8	2e-21	Prostate cancer
30	GCST90428117_32	10q11	RPL23AP61 - AGAP7P	10	3e-20	Prostate cancer
31	GCST90399469_3	8p21	NKX3-1	8	5e-19	Prostate cancer
32	GCST90428117_33	8q24	PCAT1	8	3e-19	Prostate cancer
33	GCST000154_1	8q24	CASC8 - CASC11	8	3e-19	Prostate cancer
34	GCST90399469_10	10q11	MSMB	10	4e-18	Prostate cancer
35	GCST001942_11	6q25	RGS17	6	4e-18	Prostate cancer
36	GCST90428117_34	17q21	LINC02086	17	2e-18	Prostate cancer
37	GCST90428117_35	8p21	NKX3-1	8	2e-18	Prostate cancer
38	GCST000152_3	19q13	KLK3 - KLK2	19	2e-18	Prostate cancer
39	GCST000488_18	17q12	HNF1B	17	3e-18	Prostate cancer
40	GCST90428117_36	17q21	CDK5RAP3	17	4e-18	Prostate cancer
41	GCST90428117_37	11q13	TPCN2	11	5e-18	Prostate cancer
42	GCST90428117_38	22q13	BIK	22	5e-18	Prostate cancer
43	GCST90428117_42	17q21	SKAP1	17	2e-16	Prostate cancer
44	GCST000488_19	17q21	CASC17	17	2e-16	Prostate cancer
45	GCST000488_8	4q22	PDLIM5	4	4e-15	Prostate cancer
46	GCST001148_4	2p11	VAMP8	2	3e-15	Prostate cancer
47	GCST001942_15	14q24	FERMT2	14	2e-14	Prostate cancer
48	GCST90428117_47	4q24	TET2	4	9e-14	Prostate cancer
49	GCST90428117_46	5p15	CTD-2194D22.4	5	5e-14	Prostate cancer
50	GCST90428117_44	11q13	ASCL2	11	2e-14	Prostate cancer

Gene	HGNC	Protein Function	GWAS Signal	Mendelian Role	Inheritance
HOXB13	HGNC:5112	Homeobox TF	p=1e-38	Hereditary prostate cancer	AD
ATM	HGNC:795	Ser/Thr kinase (DDR)	p=8e-9	Prostate cancer susceptibility	AD
MSH2	HGNC:7325	Mismatch repair	GWAS + ClinVar	Lynch syndrome / PCa risk	AD
MSH6	HGNC:7329	Mismatch repair	GWAS + ClinVar	Lynch syndrome / PCa risk	AD
MLH1	HGNC:7127	Mismatch repair	GWAS + ClinVar	Lynch syndrome / PCa risk	AD
PMS2	HGNC:9122	Mismatch repair	ClinVar	Lynch syndrome / PCa risk	AD
NBN	HGNC:7652	MRN complex (DDR)	ClinVar	Nijmegen breakage / PCa risk	AD
MRE11	HGNC:7230	DSB repair nuclease	ClinVar	Ataxia-telangiectasia-like / PCa	AD
FANCC	HGNC:3584	FA core complex	ClinVar	Fanconi anemia / PCa risk	AD
BIK	HGNC:1051	Pro-apoptotic (BH3)	p=5e-18	PCa susceptibility	AD
XPO7	HGNC:14108	Nuclear export	GWAS	PCa susceptibility	AD
ULK4	HGNC:15784	Pseudokinase	GWAS	PCa susceptibility	AD
RAPGEF4	HGNC:16626	cAMP-GEF	GWAS	PCa susceptibility	AD
RNASEH2B	HGNC:25671	RNase H2 subunit	GWAS	Aicardi-Goutieres / PCa	AD
ARTN	HGNC:727	GDNF ligand	GWAS	PCa susceptibility	AD

Additional ClinVar genes with both GWAS and Mendelian evidence	Highest-confidence targets (GWAS + Mendelian + Coding)
BRCA2 (HGNC:1101), AR (HGNC:644), PTEN (HGNC:9588), TP53 (HGNC:11998), SPOP (HGNC:11254), FOXA1 (HGNC:5021).
	HOXB13, ATM, BRCA2, MSH2, MSH6, MLH1

#	Gene	HGNC	UniProt	Protein Name	Evidence Tier	Mendelian
1	HOXB13	HGNC:5112	Q92826	Homeobox protein Hox-B13	Tier 1 (coding)	Y
2	KLK3	HGNC:6364	P07288	Prostate-specific antigen (PSA)	Tier 1 (coding)	N
3	MSMB	HGNC:7372	P08118	Microseminoprotein beta (PSP94)	Tier 2 (UTR)	N
4	HNF1B	HGNC:11630	P35680	HNF1 homeobox B	Tier 3 (regulatory)	N
5	NKX3-1	HGNC:7838	Q99801	Homeobox protein Nkx-3.1	Tier 3 (regulatory)	N
6	TERT	HGNC:11730	O14746	Telomerase reverse transcriptase	Tier 2 (promoter)	N
7	ATM	HGNC:795	Q13315	Serine-protein kinase ATM	Tier 3	Y
8	ITGA6	HGNC:6142	P23229	Integrin alpha-6	Tier 4	N
9	JAZF1	HGNC:28917	Q86VZ6	JAZF zinc finger 1	Tier 4	N
10	SLC22A3	HGNC:10967	O75751	Organic cation transporter 3	Tier 4	N
11	EHBP1	HGNC:29144	Q8NDI1	EH domain binding protein 1	Tier 4	N
12	LMTK2	HGNC:17880	Q8IWU2	Lemur tyrosine kinase 2	Tier 4	N
13	PDLIM5	HGNC:17468	Q96HC4	PDZ and LIM domain 5	Tier 4	N
14	THADA	HGNC:19217	Q6YHU6	THADA armadillo repeat	Tier 4	N
15	CTBP2	HGNC:2495	P56545	C-terminal binding protein 2	Tier 4	N
16	FOXP4	HGNC:20842	Q8IVH2	Forkhead box P4	Tier 3	N
17	TET2	HGNC:25941	Q6N021	Methylcytosine dioxygenase TET2	Tier 3	N
18	EEFSEC	HGNC:24614	P57772	Selenocysteine elongation factor	Tier 4	N
19	ZNF652	HGNC:29147	Q9Y2D9	Zinc finger protein 652	Tier 3	N
20	RFX6	HGNC:21478	Q8HWS3	Regulatory factor X6	Tier 4	N
21	GGCX	HGNC:4247	P38435	Vitamin K-dependent gamma-carboxylase	Tier 4	N
22	VAMP8	HGNC:12647	Q9BV40	VAMP8	Tier 4	N
23	SLC22A2	HGNC:10966	O15244	Organic cation transporter 2	Tier 4	N
24	CHD3	HGNC:1918	Q12873	Chromodomain helicase CHD3	Tier 4	N
25	EML4	HGNC:1316	Q9HC35	EML4	Tier 4	N
26	MSH2	HGNC:7325	P43246	DNA mismatch repair Msh2	Tier 3	Y
27	MSH6	HGNC:7329	P52701	DNA mismatch repair Msh6	Tier 3	Y
28	MLH1	HGNC:7127	P40692	DNA mismatch repair Mlh1	Tier 3	Y
29	PMS2	HGNC:9122	P54278	Mismatch repair PMS2	Tier 3	Y
30	NBN	HGNC:7652	O60934	Nibrin	Tier 4	Y
31	MRE11	HGNC:7230	P49959	DSB repair MRE11	Tier 4	Y
32	FANCC	HGNC:3584	Q00597	Fanconi anemia group C	Tier 4	Y
33	BIK	HGNC:1051	Q13323	BCL2 interacting killer	Tier 4	Y
34	TRIM8	—	—	Tripartite motif 8	Tier 4	N
35	FERMT2	—	—	Fermitin family member 2	Tier 4	N
36	RAD51B	—	—	RAD51 paralog B	Tier 4	N
37	KCNN3	—	—	KCa2.3 channel	Tier 4	N
38	MMP7	—	—	Matrix metalloproteinase-7	Tier 4	N
39	TPCN2	—	—	Two pore calcium channel 2	Tier 4	N
40	SPINT2	—	—	Serine protease inhibitor	Tier 4	N
41	AR*	HGNC:644	P10275	Androgen receptor	ClinVar	Y
42	BRCA2*	HGNC:1101	P51587	BRCA2	ClinVar	Y
43	PTEN*	HGNC:9588	P60484	PTEN phosphatase	ClinVar	Y
44	TP53*	HGNC:11998	P04637	Tumor protein p53	ClinVar	Y
45	SPOP*	HGNC:11254	O43791	Speckle-type POZ protein	ClinVar	Y
46	FOXA1*	HGNC:5021	P55317	Forkhead box A1	ClinVar	Y
47	CDK12*	HGNC:24224	Q9NYV4	Cyclin-dependent kinase 12	ClinVar	N
48	RB1*	HGNC:9884	P06400	Retinoblastoma protein	ClinVar	N
49	MYC*	HGNC:7553	P01106	Myc proto-oncogene	8q24 region	N
50	ALK	—	—	ALK receptor tyrosine kinase	Tier 4	N

Prostate Cancer: GWAS to Drug Target Druggability Analysis

Structured Data Sources

Database	Identifier	Name
MONDO	MONDO:0008315	Prostate cancer (hereditary/familial)
MONDO	MONDO:0005159	Prostate carcinoma
MONDO	MONDO:0021259	Prostate neoplasm
EFO	EFO:0001663	Prostate carcinoma
MeSH	D011471	Prostatic Neoplasms
HPO	HP:0012125	Prostate cancer
HPO	HP:0100787	Prostate neoplasm
OMIM	Via HGNC:5112 (HOXB13) → MIM link	Hereditary prostate cancer (HPC1-like)

Tier	Description	Count	%	Key Loci
Tier 1	Coding variants (missense)	3	6%	HOXB13 (G84E rs138213197), KLK3, GGCX
Tier 2	Splice/UTR variants	4	8%	MSMB (5'UTR), TERT (promoter), VAMP8, SPINT2
Tier 3	Regulatory variants	18	36%	8q24 enhancer region, NKX3-1, HNF1B, TET2, SLC22A3, RGS17
Tier 4	Intronic/intergenic	25	50%	ITGA6, EHBP1, PDLIM5, THADA, JAZF1, FERMT2, CTBP2

Gene	UniProt	InterPro Family	Category	Druggable?
AR	P10275	Nuclear hormone receptor (NR3C4)	Nuclear Receptor	YES ★
ATM	Q13315	PI3K-related kinase (PIKK)	Kinase	YES ★
CDK12	Q9NYV4	Cyclin-dependent kinase	Kinase	YES ★
LMTK2	Q8IWU2	Ser/Thr-Tyr protein kinase	Kinase	YES ★
KLK3	P07288	Serine protease S1A (Peptidase)	Protease	YES ★
GGCX	P38435	Vitamin K-dependent carboxylase	Enzyme	YES ★
TET2	Q6N021	Dioxygenase (2OG-Fe(II))	Enzyme	YES ★
PTEN	P60484	Protein tyrosine phosphatase	Phosphatase	YES ★
TERT	O14746	Reverse transcriptase	Enzyme	YES ★
SLC22A3	O75751	MFS transporter (OCT3)	Transporter	YES ★
SLC22A2	O15244	MFS transporter (OCT2)	Transporter	YES ★
ITGA6	P23229	Integrin alpha	Adhesion receptor	YES
KCNN3	—	KCa channel	Ion Channel	YES ★
TPCN2	—	Two-pore channel	Ion Channel	YES ★
MMP7	—	Matrix metalloproteinase	Protease	YES ★
ALK	—	Receptor tyrosine kinase	Kinase	YES ★
EML4	Q9HC35	EML4-ALK fusion	Kinase fusion	YES
HOXB13	Q92826	Homeodomain TF	Transcription Factor	Difficult
HNF1B	P35680	Homeodomain TF	Transcription Factor	Difficult
NKX3-1	Q99801	Homeodomain TF	Transcription Factor	Difficult
FOXP4	Q8IVH2	Forkhead TF	Transcription Factor	Difficult
FOXA1	P55317	Forkhead TF	Transcription Factor	Difficult
ZNF652	Q9Y2D9	Zinc finger TF	Transcription Factor	Difficult
RFX6	Q8HWS3	RFX-type TF	Transcription Factor	Difficult
TP53	P04637	p53 tumor suppressor	TF / PPI hub	Difficult (indirect)
MYC	P01106	bHLH transcription factor	TF / PPI hub	Difficult (indirect)
CTBP2	P56545	Transcriptional corepressor	Scaffold	Difficult
CHD3	Q12873	Chromatin remodeler (NuRD)	Epigenetic	Moderate
SPOP	O43791	E3 ubiquitin ligase adaptor	PPI	Moderate
MSH2	P43246	MutS DNA repair ATPase	DNA repair	Moderate
MLH1	P40692	MutL DNA repair	DNA repair	Moderate
MSMB	P08118	Immunoglobulin-like (secreted)	Secreted protein	Unknown
PDLIM5	Q96HC4	PDZ-LIM scaffold	Scaffold	Difficult
EHBP1	Q8NDI1	EH domain binding	Scaffold	Difficult
THADA	Q6YHU6	ARM repeat	Unknown function	Unknown

Category	Count	%
Druggable (Kinases, Receptors, Enzymes, Transporters, Channels, Proteases)	17	34%
Difficult (TFs, Scaffolds, PPI hubs)	14	28%
Moderate (DNA repair, E3 ligase)	4	8%
Unknown	15	30%

Gene	Expression Breadth	Present Calls	Max Score	Prostate Relevance	Specificity
AR	Ubiquitous	250	97.5	HIGH - drives PCa biology	Low specificity
HOXB13	Broad	38	92.5	HIGH - prostate-enriched	HIGH ★
KLK3 (PSA)	Known prostate-specific	—	—	HIGHEST - prostate marker	HIGHEST ★
MSMB	Known prostate-enriched	—	—	HIGH - prostate secretion	HIGH ★
NKX3-1	Known prostate-specific TF	—	—	HIGHEST - prostate lineage	HIGHEST ★
ATM	Ubiquitous	286	97.3	Moderate	Low
MSH2	Ubiquitous	278	97.6	Moderate	Low
MSH6	Ubiquitous	293	97.8	Moderate	Low
MLH1	Ubiquitous	296	94.4	Moderate	Low
NBN	Ubiquitous	299	97.4	Moderate	Low
BIK	Ubiquitous	192	93.5	Moderate	Low
TERT	Ubiquitous	105	99.6	High in cancer cells	Moderate (reactivated)
ITGA6	Ubiquitous	—	—	High in basal cells	Low
SLC22A3	Tissue-selective	—	—	Expressed in prostate	Moderate

ATM Interactor	UniProt	Score	Drugged?	Drug
CHEK2	O96017	999	Yes	Prexasertib (Phase 2)
BRCA1	P38398	999	No	—
MDC1	Q14676	997	No	—
TP53BP1	Q12888	996	No	—
MSH2	P43246	995	Moderate	—
MSH6	P52701	994	No	—
MLH1	P40692	992	No	—
TP53	P04637	975	Yes (indirect: MDM2 inhibitors)	Idasanutlin
BRCA2	P51587	972	Yes (synth. lethal: PARP-i)	Olaparib
MRE11	P49959	941	No	—
NBN	O60934	936	No	—
PTEN	P60484	893	No (target lost)	—
MYC	P01106	855	Yes (indirect)	BET inhibitors

Undrugged Gene	Interacts With	Drugged Interactor	Drug Available
NKX3-1	AR	Androgen receptor	Enzalutamide, Apalutamide
HOXB13	AR	Androgen receptor	Enzalutamide, Darolutamide
MSH6	ATM	ATM kinase	AZD0156, M4076
MLH1	MSH2	MSH2 (moderate)	—
NBN	ATM	ATM kinase	AZD0156
FOXP4	AR	Androgen receptor	Enzalutamide
FOXA1	AR	Androgen receptor	Enzalutamide
BIK	BCL2	BCL2	Venetoclax

Gene	UniProt	PDB Structures	AlphaFold	Quality (pLDDT)	Best Resolution
AR	P10275	94 (extensive)	Yes	—	1.2 Å
ATM	Q13315	14	Yes	—	2.5 Å (cryo-EM)
TERT	O14746	23	Yes (80.98)	0.60 very high	3.2 Å
KLK3	P07288	6	Yes (91.78)	0.83 very high	1.38 Å
HOXB13	Q92826	9	Yes (62.34)	0.23 very high	2.0 Å
MLH1	P40692	7	Yes	—	2.16 Å
MSH2	P43246	ChEMBL target	Yes	—	—
NKX3-1	Q99801	1 (NMR)	Yes (66.73)	0.26 very high	NMR
BRCA2	P51587	14	Yes	—	1.21 Å (peptide)
CDK12	Q9NYV4	ChEMBL target	Yes	—	—

Gene	PDB?	AlphaFold?	pLDDT	Assessment
HOXB13	Yes (9)	Yes	62.3 (moderate)	Homeodomain well-resolved
NKX3-1	Yes (1)	Yes	66.7 (moderate)	Homeodomain available
HNF1B	No	Yes	61.9 (moderate)	AF model only
MSMB	No	Yes	89.0 (high)	Good AF model
FOXP4	No	Yes	59.9 (low)	Poor model quality
JAZF1	No	Yes	70.3 (moderate)	AF model only
CTBP2	No	Yes	83.7 (high)	Good AF model
PDLIM5	No	Yes	65.0 (moderate)	Moderate AF model
LMTK2	No	Yes	47.4 (low)	Poor - mostly disordered
TET2	No	Yes	47.3 (low)	Poor - large disordered regions
THADA	No	Yes	80.1 (good)	Large ARM repeat protein

Drug	ChEMBL	Phase	Mechanism	Target Gene	GWAS Gene?
Enzalutamide	CHEMBL1082407	4	AR antagonist	AR	Y (ClinVar)
Abiraterone acetate	CHEMBL271227	4	CYP17A1 inhibitor	CYP17A1	N
Apalutamide	CHEMBL3183409	4	AR antagonist	AR	Y (ClinVar)
Darolutamide	CHEMBL4297185	4	AR antagonist	AR	Y (ClinVar)
Docetaxel	CHEMBL3545252	4	Tubulin binder	TUBB	N
Cabazitaxel	CHEMBL1201748	4	Tubulin binder	TUBB	N
Olaparib	CHEMBL521686	4	PARP inhibitor	PARP1/2	N (but targets DDR)
Niraparib	CHEMBL1094636	4	PARP inhibitor	PARP1/2	N (synth lethal w/ BRCA2)
Rucaparib	CHEMBL3833368	4	PARP inhibitor	PARP1/2	N (synth lethal w/ BRCA2)
Lu-177 vipivotide	CHEMBL4594406	4	PSMA radioligand	FOLH1	N
Leuprolide	CHEMBL1201199	4	GnRH agonist	GNRHR	N
Goserelin	CHEMBL1201247	4	GnRH agonist	GNRHR	N
Degarelix	CHEMBL415606	4	GnRH antagonist	GNRHR	N
Bicalutamide	CHEMBL409	4	AR antagonist	AR	Y (ClinVar)
Pembrolizumab	CHEMBL3137343	4	PD-1 Ab	PDCD1	N
Dutasteride	CHEMBL1200969	4	5-alpha reductase inh.	SRD5A1/2	N
Radium-223	CHEMBL2107816	4	Alpha emitter	Bone	N

Protein	ChEMBL Target	Type	Bioactivity Notes
AR	CHEMBL1871	SINGLE PROTEIN	Thousands of compounds; best-validated PCa target
ATM	CHEMBL3797	SINGLE PROTEIN	Multiple kinase inhibitors (M4076, KU-55933, AZD0156)
KLK3/PSA	CHEMBL2099	SINGLE PROTEIN	Primarily used as biomarker; some protease inhibitors
TERT	CHEMBL2916	SINGLE PROTEIN	Telomerase inhibitors (BIBR1532, imetelstat)
CDK12	CHEMBL3559692	SINGLE PROTEIN	CDK inhibitors; THZ531 selective probe
PTEN	CHEMBL2052032	SINGLE PROTEIN	Loss-of-function target; reactivation strategies
TP53	CHEMBL4096	SINGLE PROTEIN	MDM2/MDMX inhibitors for p53 reactivation
ITGA6	CHEMBL3716	SINGLE PROTEIN	Integrin-targeted antibodies and small molecules
SLC22A3	CHEMBL2073673	SINGLE PROTEIN	Organic cation transporter; drug disposition
GGCX	CHEMBL2012	SINGLE PROTEIN	Warfarin mechanism (vitamin K cycle)

Enzyme	Function	Known Inhibitors	Druggability
ATM (PI3K-related kinase)	DSB signaling	KU-55933, M4076, AZD0156	HIGH
TERT (reverse transcriptase)	Telomere maintenance	BIBR1532, imetelstat	HIGH
TET2 (dioxygenase)	DNA demethylation	Early-stage probes	MODERATE
GGCX (carboxylase)	Vitamin K-dependent	Warfarin (indirect)	MODERATE
KLK3 (serine protease)	Semen liquefaction	Peptide-based	LOW (biomarker use)
MMP7 (metalloproteinase)	ECM degradation	Broad MMP inhibitors	MODERATE

Gene	PharmGKB ID	VIP?	Key Drug-Gene Interactions
ATM	PA61	Yes	Metformin response (rs11212617); cisplatin sensitivity; PARP inhibitor response
KLK3	PA164741810	Yes	PSA levels affected by finasteride, dutasteride; screening implications
TERT	PA36447	Yes	Telomere-related drug responses; cancer therapy resistance
MLH1	PA240	Yes	5-FU response in MMR-deficient tumors; immunotherapy response
MSH2	PA31133	Yes	Immunotherapy response (MSI-H); 5-FU resistance in MMR-deficient
HOXB13	PA29388	Yes	Prostate cancer risk stratification; treatment selection
MSMB	PA31177	Yes	PSA screening accuracy modification
HNF1B	PA162391083	Yes	Diabetes drug response; cancer risk modification
JAZF1	PA162392484	Yes	Metabolic drug responses
NKX3-1	PA31645	Yes	Prostate lineage marker; treatment selection
ITGA6	PA29942	Yes	Integrin-targeting therapy response
LMTK2	PA134884391	Yes	Under investigation

Phase	Estimated Count	%
Phase 4	~100	~2%
Phase 3	~400	~7%
Phase 2	~1,500	~26%
Phase 1	~1,200	~21%
Phase 1/2	~800	~14%
Other/Observational	~1,767	~30%

Status	Count	%	Key Examples
With approved drugs (Phase 4)	8	16%	AR, KLK3(biomarker), ATM, GGCX, ITGA6, SLC22A2/3, EML4
With Phase 2-3 drugs	5	10%	TERT, CDK12, MYC(indirect), TP53(indirect), PTEN
With preclinical compounds	7	14%	LMTK2, CTBP2, TET2, VAMP8, MSH2, SPOP, TPCN2
NO drug development	30	60%	HOXB13, NKX3-1, HNF1B, MSMB, FOXP4, JAZF1, PDLIM5, etc.

Drug	Phase	Mechanism	Target Gene	GWAS Gene?
Enzalutamide	4	AR antagonist	AR	Y
Abiraterone	4	CYP17A1 inhibitor	CYP17A1	N
Docetaxel	4	Tubulin binder	TUBB	N
Cabazitaxel	4	Tubulin binder	TUBB	N
Olaparib	4	PARP inhibitor	PARP1/2	N (synth lethal)
Pembrolizumab	4	PD-1 checkpoint	PDCD1	N
Apalutamide	4	AR antagonist	AR	Y
Darolutamide	4	AR antagonist	AR	Y
Niraparib	4	PARP inhibitor	PARP1/2	N
Rucaparib	4	PARP inhibitor	PARP1/2	N
Lu-177 PSMA	4	Radioligand	FOLH1	N
Ipilimumab	4	CTLA-4 Ab	CTLA4	N
Durvalumab	4	PD-L1 Ab	CD274	N
Trametinib	4	MEK inhibitor	MAP2K1	N
Abemaciclib	4	CDK4/6 inhibitor	CDK4/6	N
Erdafitinib	4	FGFR inhibitor	FGFR	N
Temsirolimus	4	mTOR inhibitor	MTOR	N
Metformin	4	AMPK activator	Multiple	N
Berzosertib	2	ATR inhibitor	ATR	Related to ATM
Nedisertib	1	DNA-PK inhibitor	PRKDC	N
Tuvusertib	2	ATR inhibitor	ATR	Related to ATM
Veliparib	3	PARP inhibitor	PARP1/2	N
Cetrelimab	3	PD-1 Ab	PDCD1	N
MK-2206	2	AKT inhibitor	AKT	N
Pazopanib	4	Multi-kinase	VEGFR/KIT	N
Siltuximab	4	IL-6 Ab	IL6	N
Bevacizumab	4	VEGF Ab	VEGFA	N
Aspirin	4	COX inhibitor	PTGS1/2	N
Simvastatin	4	HMG-CoA reductase	HMGCR	N
Degarelix	4	GnRH antagonist	GNRHR	N

#	Pathway	Reactome ID	GWAS Genes	Druggable Nodes
1	DNA Damage Repair (DDR)	R-HSA-5693548 + children	ATM, BRCA2, MSH2, MSH6, MLH1, PMS2, NBN, MRE11, RAD51B	ATM, PARP1/2, ATR, CHK1/2
2	Mismatch Repair (MMR)	R-HSA-5358565	MSH2, MSH6, MLH1, PMS2	MSH2 (moderate)
3	Homologous Recombination	R-HSA-5685942	ATM, BRCA2, MRE11, NBN	PARP inhibitors (synth lethal)
4	TP53 Regulation	R-HSA-6804756	ATM, TP53, MDM2	MDM2 inhibitors
5	Androgen Receptor Signaling	R-HSA-5625886	AR, KLK3, FOXA1, HOXB13	AR (enzalutamide), CYP17A1
6	Telomere Maintenance	R-HSA-171319	TERT	TERT (imetelstat)
7	Cell Cycle Checkpoints	R-HSA-69473	ATM, TP53, CDK12, RB1	CDK inhibitors
8	IGF Signaling	R-HSA-381426	KLK3 (via IGFBP)	IGF1R inhibitors
9	Wnt/Beta-catenin	R-HSA-201722	TERT, CTBP2	Wnt pathway inhibitors
10	Integrin Signaling	Multiple	ITGA6, FERMT2	Integrin antibodies
11	Senescence	R-HSA-2559586	ATM, TERT	Multiple
12	Apoptosis	R-HSA-6803207	ATM, TP53, BIK	BCL2 inhibitors

#	Drug	Gene Target	Approved For	Mechanism	GWAS p-value	Priority Score
1	Venetoclax	BCL2 (BIK interactor)	CLL/AML	BCL2 inhibitor	BIK: 5e-18	9.5
2	Olaparib	PARP1 (ATM synth lethal)	Ovarian/breast	PARP inhibitor	ATM: 8e-9	9.5 ★ (already approved for mCRPC)
3	Pembrolizumab	PD-1 (MSI-H via MSH2/MLH1)	Multiple	PD-1 Ab	MSH2/MLH1: Mendelian	9.0 ★ (approved for MSI-H)
4	Imetelstat	TERT	MDS/MF	Telomerase inhib.	TERT: 3e-24	8.5
5	Crizotinib	ALK	NSCLC	ALK inhibitor	ALK: 1e-6	8.0
6	Warfarin	GGCX (VKORC1)	Anticoagulation	VitK cycle	GGCX: 1e-9	7.5
7	Abemaciclib	CDK4/6	Breast cancer	CDK inhibitor	CDK12: ClinVar	7.5
8	Metformin	AMPK/ATM pathway	Diabetes	Metabolic	ATM: 8e-9	7.0
9	Dasatinib	Multi-kinase	CML/ALL	Kinase inhibitor	Multiple	7.0
10	Trametinib	MEK1/2	Melanoma	MEK inhibitor	Pathway	6.5
11	Natalizumab	ITGA4 (related to ITGA6)	MS	Integrin Ab	ITGA6: 9e-23	6.5
12	Ruxolitinib	JAK1/2	MPN	JAK inhibitor	Pathway	6.0
13	Sirolimus	mTOR	Immunosupp.	mTOR inhibitor	PTEN pathway	6.0
14	Erdafitinib	FGFR	Bladder	FGFR inhibitor	FGF10: 4e-8	6.0
15	Celecoxib	COX-2	Arthritis	COX inhibitor	Inflammation	5.5
16	Hydroxychloroquine	Autophagy	RA/SLE	Autophagy inh.	Multiple	5.0
17	Decitabine	DNMT	MDS/AML	DNA methylation	TET2 pathway	5.0
18	Azacitidine	DNMT	MDS/AML	DNA methylation	TET2 pathway	5.0
19	Propranolol	Beta-adrenergic	Hypertension	Beta blocker	Stress pathway	4.5
20	Fulvestrant	ER	Breast cancer	ER degrader	AR cross-talk	4.5
21	Niclosamide	Multiple	Antiparasitic	Wnt/STAT3	CTBP2 pathway	4.5
22	Raloxifene	ER	Osteoporosis	SERM	Hormone pathway	4.0
23	Simvastatin	HMGCR	Hyperlipidemia	Statin	Cholesterol → androgen	4.0
24	Dapagliflozin	SGLT2	Diabetes	SGLT2 inhibitor	Metabolic	3.5
25	Aspirin	COX-1/2	Pain/CVD	COX inhibitor	Anti-inflammatory	3.5
26	Sorafenib	Multi-kinase	RCC/HCC	Kinase inhibitor	Multiple	3.5
27	Pazopanib	VEGFR/KIT	RCC	Multi-kinase	Angiogenesis	3.0
28	Golimumab	TNF-alpha	RA	TNF Ab	Inflammation	3.0
29	Ketoconazole	CYP3A4/CYP17	Antifungal	CYP inhibitor	AR pathway	3.0
30	Vandetanib	RET/VEGFR	Thyroid	Multi-kinase	Kinase pathway	2.5

Level	Description	Gene Count	%	Key Genes
Level	VALIDATED: Approved drug FOR prostate cancer	5	10%	AR (enzalutamide/apalutamide/darolutamide), ATM (via PARP inhibitors - synth lethal), MSH2/MLH1 (via
1				pembrolizumab for MSI-H)
Level	REPURPOSING: Approved drug for OTHER disease	8	16%	GGCX (warfarin), SLC22A2/3 (metformin transport), ITGA6 (integrin Abs), EML4-ALK (crizotinib), TPCN2
2				(channel drugs), KCNN3 (channel)
Level	EMERGING: Drug in clinical trials	6	12%	TERT (imetelstat), CDK12 (THZ531/CDK inhibitors), TP53 (MDM2 inhibitors), MYC (BET inhibitors), PTEN (PI3K
3				pathway), CTBP2
Level	TOOL COMPOUNDS: ChEMBL compounds but no trials	5	10%	LMTK2 (kinase probes), TET2 (early probes), VAMP8, MSH2 (early), SPOP
4
Level	DRUGGABLE UNDRUGGED: Druggable family but NO compounds	6	12%	MMP7 (protease), ALK (in PCa context), KCNN3 (ion channel), RGS17 (GPCR regulator), RAD51B (DDR), TPCN2
5	(HIGH OPPORTUNITY)			(channel)
Level	HARD TARGETS: Difficult family or unknown function	20	40%	HOXB13, NKX3-1, HNF1B, FOXP4, FOXA1, MSMB, ZNF652, RFX6, JAZF1, PDLIM5, EHBP1, THADA, EEFSEC, FERMT2,
6				TRIM8, BIK, NBN, FANCC, MRE11

#	Gene	p-value	Variant	Protein Family	Structure	Expression	Drugged Interactors	Why Undrugged	Potential
1	HOXB13	1e-38	Coding (G84E)	Homeodomain TF	PDB (9)	Prostate-specific	AR	TF - no pocket	MEDIUM (PROTAC?)
2	NKX3-1	3e-30	Regulatory	Homeodomain TF	PDB (1)	Prostate-specific	AR	TF - difficult	MEDIUM (degrader?)
3	MSMB	1e-32	UTR variant	Secreted Ig-like	AF (high)	Prostate-enriched	None direct	Novel secreted protein	LOW
4	HNF1B	5e-35	Regulatory	Homeodomain TF	AF only	Broad	None	TF - no pocket	LOW
5	BIK	5e-18	Intergenic	BH3-only (BCL2)	AF	Ubiquitous	BCL2 (venetoclax)	Small, disordered	MEDIUM (mimetic)
6	FOXP4	8e-8	Regulatory	Forkhead TF	AF (low)	Broad	AR	TF - difficult	LOW
7	JAZF1	5e-11	Intronic	Zinc finger TF	AF (moderate)	Broad	None	Novel function	LOW
8	PDLIM5	4e-15	Intronic	PDZ-LIM scaffold	AF (moderate)	Broad	None	Scaffold protein	LOW
9	EHBP1	4e-11	Intronic	EH domain binding	AF	Broad	None	Scaffold/unknown	LOW
10	THADA	5e-8	Intronic	ARM repeat	AF (good)	Broad	None	Unknown function	LOW
11	FERMT2	2e-14	Intronic	FERM domain	AF	Broad	ITGA6	Integrin pathway	MEDIUM
12	TRIM8	5e-10	Intronic	RING E3 ligase	AF	Broad	None	E3 ligase (PROTAC?)	MEDIUM
13	RAD51B	3e-10	Intronic	RecA/Rad51	AF	Broad	BRCA2, ATM	DDR - difficult	MEDIUM
14	RGS17	4e-18	Regulatory	RGS (GPCR reg.)	AF	Selective	GPCRs	Druggable family	HIGH ★
15	KCNN3	2e-8	Intronic	KCa ion channel	AF	Neural/prostate	Channel drugs	Druggable family	HIGH ★
16	TPCN2	5e-18	Intronic	TPC ion channel	AF	Broad	Channel drugs	Druggable family	HIGH ★
17	MMP7	2e-11	Regulatory	Metalloproteinase	PDB available	Tumor	MMP inhibitors	Selectivity issues	MEDIUM
18	EEFSEC	9e-7	Intronic	GTPase (EF)	AF	Ubiquitous	None	Translation factor	LOW
19	ZNF652	3e-13	Regulatory	Zinc finger TF	AF	Broad	None	TF	LOW
20	RFX6	5e-10	Intronic	RFX-type TF	AF	Pancreas/prostate	None	TF	LOW
21	NBN	Mendelian	—	FHA/BRCT scaffold	AF	Ubiquitous	ATM	DDR scaffold	LOW
22	MRE11	Mendelian	—	Metallophosphoesterase	PDB	Ubiquitous	ATM, NBN	Nuclease - difficult	MEDIUM
23	FANCC	Mendelian	—	FA core complex	AF	Ubiquitous	BRCA2	Scaffold	LOW
24	MLH1	Mendelian	—	MutL ATPase	PDB (7)	Ubiquitous	MSH2	Loss-of-function	LOW (LOF)
25	MSH6	Mendelian	—	MutS ATPase	AF	Ubiquitous	MSH2	Loss-of-function	LOW (LOF)
26	PMS2	Mendelian	—	MutL endonuclease	AF	Ubiquitous	MLH1	Loss-of-function	LOW (LOF)
27	CTBP2	3e-8	Intronic	Transcriptional corepressor	AF (high)	Broad	Multiple TFs	Corepressor	MEDIUM
28	FOXA1	ClinVar	Coding (somatic)	Forkhead TF	AF	Prostate	AR	TF pioneer factor	MEDIUM (PPI disruptor?)
29	SPINT2	1e-10	Intronic	Kunitz protease inhib.	AF	Broad	HGF/MET	Secreted	LOW
30	CDK5RAP3	4e-18	Regulatory	CDK5 regulatory	AF	Broad	CDK	Scaffold	MEDIUM

Level	Count	%
1 - Validated	5	10%
2 - Repurposing	8	16%
3 - Emerging	6	12%
4 - Tool Compounds	5	10%
5 - Druggable Undrugged	6	12%
6 - Hard Targets	20	40%

Drug	Gene	Approved For	p-value	Score
Venetoclax	BCL2 (via BIK)	CLL/AML	5e-18	9.5
Imetelstat	TERT	MDS	3e-24	8.5
Crizotinib	ALK	NSCLC	1e-6	8.0
Abemaciclib	CDK4/6	Breast	ClinVar	7.5
Metformin	AMPK/ATM	Diabetes	8e-9	7.0
Natalizumab-like	ITGA6	MS	9e-23	6.5
Erdafitinib	FGFR	Bladder	4e-8	6.0
Decitabine	DNMT/TET2	MDS	9e-14	5.0
Niclosamide	Wnt/STAT3	Antiparasitic	—	4.5
Sirolimus	mTOR/PTEN	Transplant	pathway	6.0

Gene	p-value	Family	Structure	Potential
RGS17	4e-18	RGS (GPCR regulator)	AF	HIGH
TPCN2	5e-18	Ion channel	AF	HIGH
KCNN3	2e-8	Ion channel	AF	HIGH
HOXB13	1e-38	TF (coding variant!)	PDB	MEDIUM
NKX3-1	3e-30	TF (prostate-specific)	PDB	MEDIUM
TRIM8	5e-10	E3 ligase	AF	MEDIUM
FERMT2	2e-14	FERM domain	AF	MEDIUM
MMP7	2e-11	Metalloproteinase	PDB	MEDIUM
RAD51B	3e-10	RecA recombinase	AF	MEDIUM
FOXA1	ClinVar	Forkhead TF	AF	MEDIUM

Undrugged Gene	Drugged Interactor	Drug
HOXB13 ↔ AR	Enzalutamide, Apalutamide
NKX3-1 ↔ AR	Enzalutamide, Darolutamide
FOXA1 ↔ AR	Enzalutamide
BIK ↔ BCL2	Venetoclax
NBN ↔ ATM	ATM inhibitors (M4076)
MSH6 ↔ ATM	ATM inhibitors
FOXP4 ↔ AR	AR antagonists
FERMT2 ↔ ITGA6	Integrin antibodies
MRE11 ↔ ATM	ATM inhibitors
RAD51B ↔ BRCA2	PARP inhibitors (olaparib)