[Focus on PROTAC] 118 popular targets in research

WenMandarin

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PROTAC is a new type of drug that is different from antibodies and traditional small molecule inhibitors.

The discovery of PROTAC began in 2001, when Dr.

In order to promote the small molecule PROTAC technology to the clinic, in 2013, Professor Crews established Arvinas.

With the announcement of the positive phase I clinical results of ARV-110 and ARV-471, the popularity of the PROTAC field continues to rise.

More than 100 PROTAC targets

In fact, after more than 10 years of accumulation, the scientific and industrial circles have developed thousands of PROTAC molecules.

Table 1 More than 100 PROTAC targets under development

Source: Nucleic Acids Research, PROTAC-DB; Drawing: Medicine Rubik's Cube

PROTAC molecule at the forefront

Jay Bradner, co-founder of C4 Therapeutics, said that in recent years, PROTAC has received a lot of attention because of the unique advantages of this new type of drug, including: 1) It is more selective, because this type of protein degrading agent relies on Triple action between target-PROTAC-E3 enzymes (in the human proteome, there are estimated 600 E3 ligases, and each E3 ligase has a different cell expression profile); 2) Targetable targets More broadly, because PROTAC only needs to weakly bind to the target protein to specifically "label" it (act via transient binding events), and does not need to have strong binding to the target protein (occupancy) like traditional small molecule inhibitors.

At present, the development of PROTAC drugs has entered a new stage, the clinical pipeline is rapidly expanding, and many companies are pushing candidate molecules into clinical development.

Table 2 Some PROTACs that have entered the clinic or are about to enter the clinic

Supplement: Both domestic Haisco (HSK29116) and pioneering drugs (GT20029) both have clinical applications (Source: Nature Reviews Drug Discovery)

The most popular targets: AR, BTK

AR is one of the most popular targets in the field of protein degradation and the first PROTAC molecule (ARV-110) to enter the clinic.

BTK is another popular target in the field of protein degradation.

Challenging difficult drug targets: IRAK4, BRD9

Some protein degradation agents targeting difficult drug targets are also under development, such as IRAK4.

One reason for blocking the development of IRAK4 inhibitors is that in addition to kinase activity, the protein also provides a scaffold function.

The difficult drug target that C4 Therapeutics is conquering is BRD9.

C4 Therapeutics plans to submit an IND application for the BRD9 degrading agent CFT8634 later this year to open a phase I clinical trial of the candidate molecule.

New targets for molecular glue: IKZF2, GSPT1

In addition to PROTAC, scientists have also discovered that a class of small molecules called glue degraders can also successfully induce the degradation of target proteins.

According to industry insiders, the most ideal PROTAC is actually a "molecular glue.

There have been many financing cases in the molecular glue field in the past two years.

As shown in the figure below, some molecular glue candidate products have entered the clinical development stage.
Among them, C4 Therapeutics will display the preclinical data of its molecular glue CFT7455 targeting IKZF1/3 on the upcoming AACR.
The company plans to enter the clinical development phase of CFT7455 within a few months.

Table 3 Some molecular glues that have entered or are about to enter the clinic

Source: Nature Reviews Drug Discovery

In addition to the proven targets (such as IKZF1/3), the industry is also developing molecular glues that target new targets, such as Helios (IKZF2), GSPT1.
Helios (IKZF2) is a zinc finger transcription factor that plays a role in immuno-oncology signaling and is an attractive cancer target.
The Helios (IKZF2) molecular gel degradation agent DKY709 developed by Novartis as a single agent and a phase I clinical trial in combination with Novartis' PD-1 antibody DR001 for the treatment of advanced solid tumors is underway.

CC-90009, which is being developed by BMS, is a molecular glue degradation agent targeting GSPT1.
GTPase is difficult to target because the concentration of GTP in the cell is high, and the GTP binding pocket binds strongly to GTPase, so it is difficult to develop compounds to compete with GTP.
In 2016, researchers at Celgene (acquired by BMS) reported in the journal Nature that they can use a molecular gel degrading agent that redirects CRBN to degrade GTPase GSPT1, and acute myeloid leukemia cells derived from patients are highly resistant to this drug.
sensitive.
Then, they optimized a follow-up compound, CC-90009, to maximize the degradation of GSPT1 and minimize the degradation of Ikaros, Aiolos, and other toxicity-related neosubstrates.
CC-90009 entered Phase I clinical trials in 2016.

"We have not only successfully degraded the non-drugable targets, but also brought clinical benefits to patients.
This is very exciting.
" said Mark Rolfe, senior vice president of tumorigenesis, BMS.

Stewart Fisher, CSO of C4 Therapeutics, said that for PROTAC and molecular glue, the next two years will be a critical year to verify whether a medicine can be made.

Reference materials:

1# Targeted protein degraders crowd into the clinic (Source: Nature)

2# Gaoqi Weng et al.
PROTAC-DB: an online database of PROTACs.
Nucleic Acids Research(2020).