Arvinas’ PROTAC^® Discovery Engine

Establishing new scientific frontiers by challenging the perceived limits of drug discovery

Arvinas’ platform technology is the most advanced in the field of targeted protein degradation. Arvinas’ founder, Professor Craig Crews of Yale University, was one of the inventors of targeted protein degradation and published the first paper describing PROTAC degraders in 2001.

Since our founding in 2013, Arvinas’ PROTAC Discovery Engine has been driving the most significant breakthroughs in the industry:

• Orally bioavailable degraders
• Degraders that cross the blood-brain barrier in preclinical studies
• First-in-human safety data
• First-in-human pharmacokinetic and pharmacodynamic data
• First-in-human efficacy data

Arvinas’ PROTAC Discovery Engine is Different – the Proof is in the Pipeline

Our PROTAC Discovery Engine has demonstrated the ability to create clinical-stage programs with the potential to help patients. Our drug discovery process follows three primary steps:

1. Ligase Selection and Ligand Identification

• E3 KnowledgeBase. Arvinas has deep experience in matching the right E3 ligase to the right target. The human body has more than 600 E3 ligases, and Arvinas is expanding our capabilities to include creating novel PROTAC protein degraders that recruit E3 ligases with targeted expression patterns, such as tumor or central nervous system-localized E3 ligases, where they may be beneficial for the development of targeted cancer and neurologic therapies.
• Advanced screening capabilities. Arvinas has cutting-edge high-throughput and DNA-encoded library (DEL) screening abilities, powering our ability to identify new target-binding “warheads,” including “undruggable” targets, and new binders for E3 ligases. Unlike traditional libraries, ours are designed specifically to facilitate incorporation into PROTAC protein degraders and to optimize their drug-like properties.

2. Rapid PROTAC Design

• Deep understanding of the “Zone of Ubiquitination.” Understanding how ternary complexes form between PROTAC degraders, target proteins, and E3 ligases is necessary but not sufficient. At Arvinas, we use structural and biochemical information to predict precisely which lysine residues on the target protein can be “tagged” with ubiquitin, and we design PROTAC degraders to exploit this knowledge.
• ANGLE: Arvinas Next Generation Linker Evolution. Our privileged linkers incorporate all learnings from Arvinas’ long history designing PROTAC degraders, allowing increased potency and selectivity right from the start.
• Predictive computational modeling. With our deep experience in trimer structure-based computational modeling and design algorithms, we frequently create potent degraders in the first chemical series.
• State-of-the-art proteomics capabilities. A PROTAC degrader is often far more selective than the targeting warhead. Our proteomics capabilities enable us to understand that specificity in precise detail and iterate quickly to optimize the selectivity of our degraders for the drug target.

3. Turning Degraders into Drugs

• Arvinas Rules. The long-standing “Rule of 5” has guided small molecule discovery for decades. We have discovered our own proprietary Arvinas Rules to create PROTAC degraders that, for example, are orally bioavailable and cross the blood-brain barrier.
• Deep knowledge of in vivo PK/PD and efficacy relationships. Our comprehensive understanding of molecular features that impact PROTAC biodistribution and target degradation, in the body, enables us to create PROTAC degraders with drug-like properties and activities.