Four Major Trends In The Development of PROTAC

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Four Major Trends In The Development of
PROTAC

In the context of the increasing popularity of macromolecular drugs such as monoclonal
antibody drugs, dual antibody drugs and ADCs, small molecule drugs have once again
become the focus through PROTAC (Proteolysis targeting chimera), a breakthrough new
technology.

After 20 years of development, PROTAC technology has attracted the attention of many
pharmaceutical companies, such as Pfizer, Bayer, Novartis and other multinational
pharmaceutical companies.

Professor Craig M. Crews of Yale University, co-founder of Arvinas, recently published a
review in Nature Reviews Drug Discovery that summarized the development of PROTAC
over the past 20 years. Four major development directions for PROTAC in the next
20 years are discussed.

Introduce PROTAC

Many targets that play key roles in cancer and other diseases are notoriously difficult to
become drug, some of which are difficult to bridge with small molecules due to their wide
and shallow active sites. Others have "smooth" surfaces with few sites for small molecules
to bind to.

But with the continuous development of PROTAC technology, these undruggable
targets have also become within reach.

PROTAC techonoly uses heterozygotic bifunctional small molecule compounds to bring
the target protein and the intracellular E3 ubiquitin ligase closer, and specifically degrades

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the target protein in vivo through the ubiquitin-proteasome protein degradation pathway.
The drug is composed of 3 parts, that is, one end is the specific E3 ubiquitin ligase ligand,
the other end is the specific ligand of the target protein and the linker in the middle, thus
forming the "target protein-PROTAC-E3 ubiquitin ligase".

Unlike traditional small-molecule drugs, PROTAC drugs do not need to bind tightly to the
disease-causing target for long periods of time to degrade it. By destroying protein
targets rather than inhibiting them, problems of non-drugability and drug resistance are
solved.

Table 1. PROTAC-targeted protein degraders in clinical development

Four major trends in the future development of
PROTAC

In the past few years, PROTAC technology has basically matured. The authors propose
that the next milestones in the field of PROTAC will focus on the following four
areas, namely, identifying optimal protein degradation targets, expanding the
scope of clinical application of E3 ligase, expanding the scope of clinical
treatment beyond oncology and developing other PROTAC modes.

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1. Identify optimal protein degradation targets

The first wave of clinical phase proteolytic agents selected are clinically proven mature
targets. Targeted products have been developed with moderate success, and the
potential of PROTACs as a therapeutic modality has been validated. The real promise of
the technology, however, is in enabling those undruggable targets.

In this paper, "Principles of PROTAC targets" (see figure below) are proposed, including:
changes that deviate from the natural state through overexpression, mutation,
aggregation, isomer expression or fine localization, leading to disease by means of
functional acquisition; a binding surface accessible to E3 ligases; ideally, a structure-free
region capable of accessing the proteasome.

Proteins with drug resistance mutations to targeted therapy, proteins with backbone
functions, and proteins that are "undruggable" by other therapeutic modalities may also be
suitable PROTAC targets.

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Principles of PROTAC Targets (Source: References)

2. Expand the scope of clinical application of E3 ligase

More than 600 E3 ubiquitin ligases are encoded in the human genome. However, only a
few E3 ligases (VHL, CRBN, etc.) are currently used for PROTAC design. How to expand
E3 ubiquitin ligases that can be used for PROTAC technology is also one of the
challenges PROTAC faces.

The authors propose that new E3 ligases can be found in the following ways.

A practical and valuable approach is to find broadly applicable, ubiquitous ligases, similar
to CRBN and VHL. They can be paired with any target protein, allowing unrestricted
application in multiple therapeutic indications.

Another approach, based on key characteristics of ligases, such as tissue and cell
specificity, tumor enrichment, and tumor necessity, could provide development
opportunities for domain-specific protein degradation therapies. Interestingly, some
ligases exhibit "reverse specificity" (low expression in specific tissues or cell types), which
may also present opportunities for protein degraders.

In addition, another new frontier in precisely targeting protein degradation is PROTAC
molecules that specifically target tumor cells, which can be achieved by targeting
tumor-specific or tumor-enriched E3 ligases.

3. Expanding the scope of clinical treatment beyond oncology

So far, research on protein degraders has mainly focused on the oncology field, but since
protein degraders may degrade any chosen target, their application can be broader. In
fact, in recent years, protein degraders have gradually been used in fields other than

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oncology, such as neurodegenerative diseases. And there is a breakthrough
in inflammation/immunology field.

Following the success of immune checkpoint inhibitors, the development of small
molecule drugs that can stimulate the anticancer immune response is an important area
of drug development. PROTAC molecules can activate immune cells in the mode of
small molecule drugs and mimic the effects of PD-1/PD-L1 targeted therapy, thus
becoming a potential "first-in-class" therapy. Recently, PROTAC molecules targeting
MAP4K1 have shown promising preclinical activity.

One of the key features of PROTAC molecules is their ability to degrade proteins that are
not targeted by traditional small-molecule inhibitors because they lack an active site. This
feature makes proteins that accumulate in various neurodegenerative diseases (such as
Tau) become potential targets.

4. Develop other PROTAC modes

In addition to PROTAC, various novel protein degradation technologies have been
developed, further expanding the range of targets that can be targeted by this technology.

The authors define three types of PROTACs: traditional small-molecule PROTACs,
PROTACs of peptides or other biological products ( bioPROTACs ), and PROTACs
containing both peptide and traditional small-molecule "warheads" (hybrid
PROTACs).

BioPROTACs are based on genetic coding to directly fuse peptides, fusion proteins, and
oligonucleotides with E3 ligases, which bind and degrade target proteins through peptide
or protein recognition domains. Since BioPROTAC relies on genetic coding, there are
certain limitations.

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The article pointed out that the past 20 years is prologue, and the field of targeted protein
degradation has been ""poised to challenge", challenging targets that were previously
considered "undruggable". Although there is no drug approved by the FDA so far,
PROTAC will eventually usher in its era after more than 20 years of technical
accumulation.

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References:
[1]. https://www.nature.com/articles/s41573-021-00371-6

Related articles:
[1] PROTACs VS. Tranditional Small Molecule Inhibitors
[2] PROTAC And Other Protein Degradation Technology