13 PROTACs and 5 molecular glues in the clinical development stage

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13 PROTACs and 5 molecular glues in the clinical development stage

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13 PROTACs and 5 molecular glues in the clinical development stage. 

PROTAC protein degradation agent generally consists of three parts: target protein binder, linker and E3 ubiquitin ligase binder. One end of the PROTAC molecule binds to the target protein, and the other end binds to the E3 ubiquitin ligase.

E3 ubiquitin ligase is the ubiquitination of the target protein, and the proteasome recognizes and degrades the labeled target protein. Recently, Arvinas first disclosed the structure of ARV-110 and the estrogen receptor degrading agent ARV-471 at the American Association for Cancer Research (AACR), which provides an example for people to design and synthesize orally effective PROTAC.

PROTAC advantage 1: Degrade active protein and scaffold protein. IRAK4 is a kinase that can activate both IL-1 family receptors and Toll-like receptor (TLR) inflammatory signals. Since the IRAK4 protein also functions as a scaffold, the development of IRAK4 inhibitors has been stagnant, and the emergence of degrading agents makes it a possible potential therapeutic target.

KT-474 is currently the only non-tumor degradant in clinical practice, and its research and development indications include atopic dermatitis and hidradenitis suppurativa. Kymera’s KT-413 is an IRAK4 degrader with conservative IMiD activity and will undergo cancer clinical trials later this year.

BRD9 can recognize acetylated lysines on histones and other proteins, and plays an important role in epigenetics. New data indicate that BRD9’s scaffold function may drive its role in rare sarcomas.

Although small molecules can bind and inhibit BRD9 with high selectivity, the cell activity is not ideal. The degradation of BRD9 significantly inhibited the progress of mouse tumor models.

PROTAC advantage 2: New cell selectivity. There are an estimated 600 E3 ligases in the human proteome, each with a different cell expression profile. The cell type selectivity of degradants ultimately depends on the different expression profiles of E3 ligase in the cells.

BCL-XL is an anti-apoptotic protein. Targeting BCL-XL will kill platelet cells, resulting in dose-limiting thrombocytopenic toxicity. Studies have found that the expression level of VHL ligase in platelets is very low.

As a BCL-XL degrading agent, DT2216 has a good anti-tumor effect while retaining platelet activity. Currently, clinical trials for T-cell lymphoma and small cell lung cancer are underway.

At present, at least 13 PROTAC drugs have entered the clinical stage, and the targets include AR, ER, BCL-XL, IRAK4, STAT3, BTK, TRK, BRD9, etc.:

PROTAC currently in the clinical stage

In addition to PROTAC, molecular glue (glue degrader) can also successfully induce the degradation of target proteins.

Molecular glue degradation agents are small molecules that can induce the interaction between the E3 ubiquitin ligase substrate receptor and the target protein, thereby leading to the degradation of the target protein.

Thalidomide anticancer drugs are a typical representative of molecular glues. Such drugs can redirect the E3 ubiquitin ligase CRBN, so that the transcription factors IKZF1 and IKZF3 are polyubiquitinated and degraded by the proteasome.

There are currently 5 molecules in the clinical research stage, the targets include IKZF2, IKZF1/3, GSPT1, etc.:

Molecular glue currently in clinical stage

Bifunctional degradation agents can pre-select a target and then look for related ligands to capture it.

In contrast, molecular glue is limited by a small part of the activity spectrum of E3 molecules that has been determined so far.

So far, only about “24 to 30” new IMiD substrates have been reported, but “the final statistics will be much higher than this number.”

(source:internet, reference only)

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