Eli Lilly's $1.6 billion layout opens up a new world of targeted therapy, do you know these new developments?

Today, Eli Lilly and Company and Lycia Therapeutics announced a multi-year R&D cooperation and licensing agreement
.

Lycia was co-founded by Professor Carolyn R.
Bertozzi of Stanford University, the winner of the "MacArthur Genius Award".
Soon after stepping out of the hidden mode in June last year, it was rated as worthy of attention by the C&EN website under the American Chemical Society (ACS) in 2020 One of the 10 start-up companies
.

Targeted degradation of extracellular and cell membrane proteins

At present, targeted protein degradation therapies including PROTAC molecules and molecular glues have received extensive attention
.

However, most of the target proteins degraded by the proteasome are intracellular proteins, and about 40% of the proteins in the human proteome are extracellular proteins and cell membrane proteins
.

In July 2020, Professor Bertozzi's research team published a breakthrough study in the journal Nature, introducing a protein degradation technology called LYTAC
.

▲Illustration of LYTAC protein degradation technology and PROTAC and other protein degradation technologies (picture source: reference [2])

However, there is still a long way to go for the development of degradation technologies that target the degradation of extracellular proteins into candidate therapies that can enter clinical trials
.

Tissue specific LYTAC protein degradation agent

Scientific innovation has not stopped.
In March of this year, the research team of Professor Bertozzi and the research team of Professor Weiping Tang of the University of Wisconsin–Madison published papers respectively
.

In these two studies, scientists linked specific N-acetylgalactosamine (GalNAc) with antibodies or peptides that target extracellular proteins
.

These two studies have shown that coupling GalNAc with antibodies or polypeptides targeting extracellular proteins can also successfully guide the phagocytosis of extracellular proteins by hepatocytes, thereby completing tissue-specific degradation of LYTAC
.

▲The LYTAC degradation agent made by GalNAc coupling can mediate liver-specific protein degradation (picture source: reference [4])

Moreover, Professor Bertozzi’s research team found that a chemically synthesized polypeptide chain with a molecular weight of 3.
4 kDa coupled with GalNAc can effectively mediate the degradation of a variety of tumor-related integrins and inhibit tumor cell line growth in in vitro experiments.
Grow
.

Small molecule degradation agent targeted to degrade extracellular proteins

Last week, the research team of Professor David Spiegel from the Department of Chemistry at Yale University published a paper on Nature Chemical Biology, introducing a small molecule degradation agent called MoDE-A
.
One end of this bifunctional molecule is composed of GalNAc, which can bind to the ASGPR on the surface of liver cells, and the other end can bind to the target protein outside the cell to mediate the engulfment of the target protein by the cell and send it to the lysosome for degradation
.
This bifunctional molecule does not contain polypeptide or protein components and can be completely chemically synthesized
.
In this study, cell culture and animal experiments showed that they can effectively mediate the degradation of extracellular antibodies
.

▲Design and chemical structure of MoDE-A, a small molecule degrading agent targeted to degrade extracellular proteins (picture source: reference [3])

A review article published by Nature Chemical Biology pointed out that the discovery of GalNAc-LYTAC and MoDE-A represents a significant advancement in the field of targeted protein degradation based on lysosomes
.
At the same time, these studies also pointed out the direction of advancing LYTAC technology to clinical development
.
Although most of the current LYTAC molecules are based on antibodies that bind to the target protein, the success of peptides LYTAC and MoDE-A means that peptides and small molecules can be the starting point for optimization of LYTAC protein degradation agents
.
These smaller molecular weight LYTAC degradation agents are expected to bring better internalization and degradation efficiency, and may be the key to achieving better pharmacokinetic indicators and oral bioavailability
.

However, the stability of the current MoDE-A is not high, and further optimization is still needed
.
Even so, the author of the review article stated that these advances paved the way for further clinical development of LYTAC protein degradation agents
.

Attachment: the characteristics of different targeted protein degradation technologies

Reference materials:

[1] Lilly and Lycia Therapeutics Enter into Strategic Collaboration to Discover and Develop Novel Lysosomal Targeting Chimera (LYTAC) Degraders.
Retrieved August 25, 2021, from https://investor.
lilly.
com/news-releases/news-release-details /lilly-and-lycia-therapeutics-enter-strategic-collaboration

[2] Lysosome-targeting chimeras evolve.
Retrieved August 25, 2021, from https:// Caianiello et al.
, (2021).
Bifunctional small molecules that mediate the degradation of extracellular proteins.
Nature Chemical Biology, https://doi.
org/10.
1038/s41589-021-00851-1

[4] Ahn et al.
, (2021).
LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation.
Nature Chemical Biology, https://doi.
org/10.
1038/s41589-021-00770-1

[5] Banik et al.
, (2020).
Lysosome-targeting chimaeras for degradation of extracellular proteins.
Nature, https://doi.
org/10.
1038/s41586-020-2545-9

[6] New class of molecule targets proteins outside cells for degradation.
Retrieved August 25, 2021, from https:// Ding et al.
, (2020), Emerging New Concepts of Degrader Technologies.
Trends Pharmacol Sci.
, doi: 10.
1016/j.
tips.
2020.
04.
005

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