# The first PROTAC: a chimeric molecule that tags a protein for destruction

Source: https://onco.cc/key-papers/paper-protac-concept-sakamoto-pnas-2001/  
OnCo record `paper-protac-concept-sakamoto-pnas-2001` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Crews and Deshaies built a two-headed molecule linking a ligand for the target protein MetAP-2 to a peptide recognised by an E3 ubiquitin ligase, and showed it induced ubiquitination and degradation of the target, founding targeted protein degradation.

## Summary

The proteolysis-targeting chimera (Protac-1) joined ovalicin, which binds methionine aminopeptidase-2, to the IkappaBalpha phosphopeptide recognised by the SCF-beta-TRCP E3 ligase. In Xenopus egg extracts, Protac-1 recruited MetAP-2 to the ligase and triggered its ubiquitination and proteasomal degradation.

The paper established the principle that a bifunctional molecule can hijack the cell's own disposal machinery to eliminate a chosen protein, including proteins with no enzymatic activity to inhibit. Peptide-based PROTACs were poorly cell-permeable; the field became practical when all-small-molecule degraders using VHL and cereblon ligands appeared (Bondeson 2015; Winter 2015, dBET1 degrading BRD4 in vivo).

Degraders now include vepdegestrant (oestrogen receptor), ARV-110 and other androgen-receptor degraders, and the molecular glues (lenalidomide-class drugs) reinterpreted through the same mechanism.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: PNAS
- Year: 2001
- DOI: 10.1073/pnas.141230798
- Authors: Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ
- Findings: Protac-1 induced ubiquitination and degradation of MetAP-2 in cell extracts by recruiting the SCF E3 ligase; Degradation required both halves of the chimera and an intact ubiquitin-proteasome pathway; Introduced the terminology and concept of proteolysis-targeting chimeras; Small-molecule successors (2015 onwards) achieved in vivo degradation of BRD4 and other targets at nanomolar potency
- What it means: Instead of blocking a cancer protein, a drug can now remove it entirely, which works even for proteins without a druggable active site and can overcome resistance driven by target overexpression or mutation. Several degraders are in late-stage trials for breast and prostate cancer.
- Caveats: The original molecule was a large peptide conjugate with no cell permeability; clinical degraders took 15 years; Degraders are large molecules with challenging oral bioavailability and pharmacokinetics; Ligase expression varies between tissues and tumours, and resistance via ligase loss has been documented; Clinical superiority over inhibitors has so far been modest in the first phase 3 readouts (for example vepdegestrant)

## Sources

- DOI: https://doi.org/10.1073/pnas.141230798
- In vivo small-molecule degrader dBET1 (Winter 2015): https://doi.org/10.1126/science.aab1433

## Connected records

- technologies: [Degrader-antibody conjugate (DAC)](https://onco.cc/technologies/degrader-antibody-conjugate/), [Molecular glue discovery platforms](https://onco.cc/technologies/molecular-glue-platforms/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)
- fronts: [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [Estrogen receptor (ERα)](https://onco.cc/targets/estrogen-receptor/)
- drugs: [Vepdegestrant](https://onco.cc/drugs/vepdegestrant/)
- trials: [VERITAC-2](https://onco.cc/trials/veritac-2/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- journals: [Proceedings of the National Academy of Sciences](https://onco.cc/journals/pnas/)

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