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Module 0

The Druggable Genome & Modalities Landscape

Of ~20 000 human protein-coding genes, only ~3 000 are considered druggable with today’s modalities. This module maps that space: target classes (GPCRs, kinases, proteases, ion channels, transcription factors), modality taxonomy (small molecule, biologic, nucleic acid, cell/gene therapy), and the regulatory pathways at FDA and EMA. It sets up modules 1–8, each of which examines one modality in depth.

1. The Druggable Genome

Hopkins & Groom 2002 coined the term for the subset of human proteins to which small molecules can bind with sufficient affinity and specificity for therapeutic use. Subsequent estimates (Santos 2017, Finan 2017) refine the list to ~3 000 targets — ~1 500 addressed by approved drugs, ~1 500 plausible but undrugged. Classical druggable classes: GPCRs (~800), kinases (~550), proteases (~600), ion channels (~400), nuclear receptors (~50). Non-druggable classes (transcription factors, protein-protein interactions, RAS, MYC) were the 30-year frontier — now partially opened by PROTACs (M2) and molecular glues.

2. Modality Landscape

A modality is a therapeutic technology class. Rising complexity:

  • Small molecules — oral, cheap, but limited to protein targets with suitable pockets.
  • Biologics / antibodies — high specificity, IV administration, expensive.
  • Antibody-drug conjugates (ADCs) (M3) — antibody targeting + cytotoxic payload.
  • PROTACs & molecular glues (M2) — co-opt degradation machinery.
  • Cell therapy (CAR-T) (M4) — engineer patient’s own lymphocytes.
  • mRNA, siRNA, ASO (M5) — encode or silence proteins.
  • CRISPR (M6) — permanent genome edit.
  • Gene therapy (AAV, lentiviral) (M7) — deliver functional copies.
  • Theranostics (M8) — radionuclide diagnosis + therapy pairs.

Simulation: Modality Approvals

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3. Regulatory Pathways

FDA and EMA have adapted to new modalities: Breakthrough Therapy designation (2012), RMAT (Regenerative Medicine Advanced Therapy, 2016), Fast Track, and Accelerated Approval pathways compress timelines for high-unmet-need indications. Cell and gene therapies use OTAT (FDA) / CAT (EMA) for specialised review. Cost and reimbursement questions — $2.1 M Zolgensma, ~$2.2 M Casgevy — are reshaping how payer systems think about one-time curative therapies.

Key References

• Hopkins, A. L. & Groom, C. R. (2002). “The druggable genome.” Nat. Rev. Drug Discov., 1, 727–730.

• Santos, R. et al. (2017). “A comprehensive map of molecular drug targets.” Nat. Rev. Drug Discov., 16, 19–34.

• Finan, C. et al. (2017). “The druggable genome and support for target identification and validation in drug development.” Sci. Transl. Med., 9, eaag1166.

• Pharmaprojects / Citeline (2024). R&D Annual Review.

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