Novel PROTAC, SPNpro

Immunometabolism involves glycolysis, tricarboxylic acid cycle, and pentose phosphate pathway and amino acid metabolism and other intracellular metabolic pathways, which play a vital role in regulating immune cell responses. In particular, the metabolism of amino acids such as tryptophan (Trp), arginine, glutamine, and leucine can affect tumor progression and immune cell proliferation and differentiation. Therefore, by regulating the enzymes related to the metabolism of these amino acids, scientists have been trying to develop immunometabolic cancer therapies. However, traditional small molecule inhibitors that target these enzymes usually cannot produce a durable response due to drug resistance. In addition, some non-druggable enzymes cannot be targeted by traditional small molecule inhibitors. Therefore, there is an urgent need to explore alte
ative methods to interfere with amino acid metabolism.

PROTAC (proteolysis targeting chimeras) is a new type of drug different from traditional small molecule inhibitors. It consists of target protein binder, linker, and E3 ubiquitin ligase binder. The protein-proteasome system mediates the degradation of target proteins and provides another way to regulate protein homeostasis. Specifically, one end of the PROTAC molecule (https://www.creative-biolabs.com/protac/) binds to the target protein, and the other end binds to the E3 ubiquitin ligase that can mark the target protein as defective or damaged by attaching a small protein called ubiquitin to it. After that, the cell's protein shredder (i.e., the proteasome) recognizes and degrades the labeled target protein. Based on this mechanism of action, drugs developed based on PROTAC technology are also called protein degradants.

One of the advantages of PROTAC technology is the ability to change the target from undruggable to druggable. Overcoming the resistance of traditional small molecule inhibitors is another potential advantage.

So far, PROTAC has been used to target a variety of proteins, including AR, BTK, BRD2-4, and CDK4/6. However, there are not many studies on using PROTAC to target immune metabolism-related proteins.

In a study published in Nature Communications on May 18, a team of scientists from Singapore's Nanyang Technological University developed a new type of PROTAC targeting indoleamine 2,3-dioxygenase that can be activated intelligently, semiconducting polymer nano-PROTAC (SPNpro). Studies have confirmed that SPNpro cleverly combines the anti-cancer and protein degradation anti-cancer powers of optical therapy, effectively inhibiting tumor growth and metastasis in mice models. At the same time, the potential off-target side effects of current PROTAC molecules were overcome in this study.

SPNpro consists of a semiconductor polymer core coupled with a PROTAC fragment through a cancer-biomarker-cleavable peptide.
Semiconductor polymer nanoparticles (SPNs) have good biocompatibility and adjustable optical properties, so they are used by scientists for the development of optical therapy.

The specific mechanisms of SPNpro's action are as follows. On the one hand, after systemic administration, SPNpro can passively accumulate in live mouse tumors to eliminate tumor cells and induce the release of tumor-associated antigens and immunogenic cell death (ICD). These released tumor-associated antigens further induce DC maturation and promote T cell activation, thereby enhancing the anti-tumor T cell immune response.

At the same time, the PROTAC function of SPNpro can be specifically activated by the cancer biomarker CatB. In live mice, the tumor-expressed CatB can cleave SPNpro in situ and release the IDO-targeted PROTAC peptide (IPP). The activated IPP binds to the immunosuppressive IDO, thereby inducing its degradation, which can alleviate the excessive consumption of tryptophan and the accumulation of kynurenine (Kyn), thereby reversing immune suppression and promoting the activation of effector T cells.

Finally, SPNpro-mediated in situ immune metabolic intervention and immunogenic optical therapy effectively enhance the anti-tumor T cell immune response and inhibit tumor growth and metastasis.

In summary, the research provides a new combination therapy model to fight cancer. At the same time, through the design of SPNpro, scientists made new progress in solving the always-on bioactivity and off-target side effects of traditional PROTAC. In addition, such PROTAC design (https://www.creative-biolabs.com/protac/protac-molecule-discovery.htm) can also be used for other immune metabolism-related target proteins, such as glutaminase, arginase, fatty acid synthase, lactate dehydrogenase, and acetyl-CoA acetyltransferase, providing new opportunities for the development of PROTAC in cancer treatment.