Company: ARVN
Filing Date: 2025-02-11
Form Type: 10-K
Source: 0001655759-25-000016
Chunk: 89

Company: ARVINAS, INC.
Filing Date: 2025-02-11
Form: 10-K
Item: Item 1
Chunk 89
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 know-how, and intellectual property and comprises three stages:

14

Ligase Selection and Ligand Identification

•E3 KnowledgeBase - The human body has more than 600 E3 ligases, and we select ligands for E3 ligases from our proprietary library for incorporation into our PROTAC targeted protein degraders. We continue to research additional E3 ligases that are expressed in specific tissues or diseases, and identify or discover associated binding ligands, to create novel PROTAC protein degraders that recruit E3 ligases with targeted expression patterns, such as tumor or central nervous system-localized E3 ligases, that may be beneficial for the development of targeted oncologic and neurologic therapies. To enable targeted protein degradation via alternative E3 ligases, we have discovered and characterized novel small molecule ligands targeting the E3 ligase KLHDC2. We have functionalized these novel KLHDC2-targeting small molecules into robust and potent PROTAC KLHDC2-degraders and demonstrate KLHDC2-dependent degradation of target proteins across cell lines. Furthermore, we have leveraged biochemical studies to understand mechanistic assembly of the KLHDC2 holo-E3 complex together with its cognate adapter proteins in addition to structural studies to show the dynamic tetramer formation of KLHDC2 E3 assemblies induced by small molecule engagement. In doing so, we have expanded the arsenal of E3 ligases that can be targeted by small molecules and may be hijacked for targeted protein degradation. We believe our success with the diverse set of E3 ligases that we are currently employing and the binders of other E3 ligases that we are researching provide us with a competitive advantage as we develop a range of products with different technical characteristics. 

•Advanced Screening Capabilities - We select ligands for incorporation into our PROTAC targeted protein degraders from a variety of sources. The ligands we select, which target the desired protein for degradation or E3 ligase for incorporation into our PROTAC targeted protein degraders, may include (1) de novo ligands discovered through high-throughput screening, biophysical directed binding approaches, virtual or in silico computer-based screening, and affinity-based hit identification through our in-house DNA-encoded libraries that that are tailored to the needs of incorporation into PROTAC protein degraders and to optimize their drug-like properties or (2) ligands that are known to bind protein targets but may have faced therapeutic limitations that we believe our PROTAC technology can overcome, such as