Novartis Bets $1.3 Billion on Dunad Therapeutics' Novel Monovalent Protein Degradation Platform

Today, Dunad Therapeutics announced a research and development collaboration agreement with Novartis to jointly develop next-generation oral targeted protein degradation therapies. Dr. Jay Bradner, President of the Novartis Institutes for BioMedical Research (NIBR), said in a tweet: "We can't wait to apply this chemistry to tackle serious diseases."

Dr. Jay Bradner is an expert in the field of protein degradation and a co-founder of C4 Therapeutics, a company focused on the development of protein degradation therapeutics. Under his leadership, the NIBR team has developed dozens of targeted protein degradation compounds. So, what makes him optimistic about Dunad Therapeutics' technology?

Dunad Therapeutics' unique platform is designed to develop monovalent small-molecule drugs that induce the selective degradation of pathogenic proteins. These agents solely require binding to the target protein to trigger its specific degradation. Currently, targeted protein degradation has emerged as a highly prominent field in novel drug development. However, many existing protein degraders are bifunctional molecules: one end binds to the target protein, while the other binds to an E3 ubiquitin ligase, recruiting the ligase into proximity with the target to attach ubiquitin "tags," thereby promoting the target's degradation via cellular lysosomes. PROTAC molecules represent a class of such bifunctional compounds, and several PROTAC candidates have already achieved clinical proof of concept.

However, due to the incorporation of multiple protein-binding moieties, these bifunctional or multifunctional molecules typically exhibit high molecular weights and complex chemical designs, which may hinder their ability to cross the cell membrane and exert intracellular effects.

The concept of monovalent protein degraders is not novel; the development of selective estrogen receptor degraders (SERDs) has spanned many years. Furthermore, a recent study published by Genentech in *Cancer Discovery* demonstrates that inavolisib, the company’s inhibitor targeting PI3Kα mutants, not only inhibits the activity of PI3Kα but also promotes its degradation. Further research revealed that oncogenic PI3Kα mutations render the protein unstable, thereby accelerating its degradation process. The binding of inavolisib to these mutants further destabilizes them, making them more susceptible to degradation. Consequently, this molecule exhibits a dual mechanism of action: it inhibits both wild-type PI3Kα and PI3Kα mutants, while specifically degrading the mutant proteins.

The significance of these studies lies in opening new avenues for targeted protein degradation, demonstrating that the process does not necessarily require multifunctional molecules. Dr. Steve Staben, head of the Genentech research team developing inavolisib, described 39 monovalent targeted protein degraders in a paper published last year in the *Journal of Medicinal Chemistry*.

Compared with multifunctional molecules, monovalent protein degraders have a lower molecular weight, which may facilitate their passage across cell membranes or the blood-brain barrier, thereby expanding the spectrum of targets amenable to protein degradation.

Dunad Therapeutics' unique platform enables high-throughput screening of potential monovalent protein degrader compounds to discover highly specific small molecules. Furthermore, this screening approach is not limited to specific target classes.

Under the collaboration agreement, Dunad Therapeutics will discover monovalent protein degraders for up to four potential targets. Novartis will provide expertise in targets and ligands, proprietary assays and models, and will hold the development rights to these programs. Dunad will receive a $24 million upfront payment and equity investment, along with research funding. It is also eligible for up to $1.3 billion in milestone payments.

References:

[1] Dunad Therapeutics enters Strategic Collaboration with Novartis to Develop Next-generation Oral Targeted Protein Degrader Therapies. Retrieved November 2, 2021, from https://www.prnewswire.com/news-releases/dunad-therapeutics-enters-strategic-collaboration-with-novartis-to-develop-next-generation-oral-targeted-protein-degrader-therapies-301413147.html.

[2] On the hunt for monomeric degraders. Retrieved November 2, 2021, from https://cen.acs.org/biological-chemistry/proteomics/hunt-monomeric-degraders/99/i40

[3] Song et al., (2021). RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (Inavolisib) efficacy. Cancer Discovery，DOI: 10.1158/2159-8290.CD-21-0072

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