PROTAC technology, by linking E3 ubiquitin ligase to the target protein, leads to the ubiquitin modification of the target protein which is broken down into peptides and amino acids by proteasome. After the target protein is degraded, PROTAC will be released for reuse and continue to destroy the target protein.
PROTAC offers various potential advantages over other drugs and therapies, such as its broad tissue dispersion and oral administration. PROTAC’s manufacturing method is easier when compared to other therapies (such as cell therapy, antibody drugs, and so on); when compared to small molecular biologics, PROTAC can hit more targets that small molecular drugs cannot, resulting in superior outcomes.
Since Yale University Professor Craig Crews initially introduced PROTAC technology in 2001, this discipline has grown significantly. Thousands of PROTAC compounds have been produced by the scientific and industry communities during the last 20 years. PROTAC drugs targeting androgen receptor (AR), estrogen receptor (ER), and Bruton tyrosine kinase (BTK) have entered clinical development in recent years. PROTAC is one of the most promising and ground-breaking drug development technologies.
Researchers from Shanghai University of Science and Technology published a paper entitled “Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation” in Cell Chemical Biology, a sub-journal of Cell.
In this study, two kinds of PROTAC molecules targeting nicotinamide phosphotransferase (NAMPT) were developed, which can degrade NAMPT protein efficiently and kill blood tumor cells effectively, outperforming NAMPT inhibitor FK866 in clinical trials.
Nicotinamide adenine dinucleotide (NAD+), an important small molecular metabolite, is widely involved in a series of biochemical reactions in cell energy metabolism, such as glycolysis, oxidative phosphorylation, and fatty acid oxidation. It also plays a variety of roles as an auxiliary substrate in signal transduction, including DNA damage repair and protein deacetylation.
Nicotinamide phosphotransferase (NAMPT) is a rate-limiting enzyme that catalyzes the synthesis of nicotinamide mononucleotides (NMN, the precursor of NAD+) from nicotinamide (NAM) in mammalian NAD+ remedial synthesis pathway. There are two forms of NAMPT, i.e., intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT).
A great number of references have proved that NAMPT plays a key role in promoting tumor cell proliferation and dedifferentiation. Due to the increased catabolism of NAD+ and ATP in tumor cells, tumor cells are more sensitive to iNAMPT inhibition than normal cells. In a variety of human malignant tumors (astrocytoma, myeloma, oral cancer, gastric cancer, endometrial cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, etc.), the level of plasma eNAMPT is increased, so eNAMPT is considered as a carcinogenic factor.
Therefore, there is an urgent need for a new strategy to target iNAMPT and eNAMPT, which is difficult to achieve by standard enzyme inhibitors. And PROTAC technology brings new hope.
In this study, the team developed two highly selective PROTAC that can rely on E3 ligase Cereblon to promote the degradation of NAMPT. The killing effect of these two kinds of PROTAC on blood tumor cells is better than that of clinical candidate drug FK866 (an enzyme inhibitor of NAMPT).
These results suggest that the targeted degradation of protein NAMPT with tumor-promoting function by PROTAC is beneficial and feasible and can achieve the effect that traditional enzyme inhibitors cannot.
PROTAC technology has advanced rapidly in recent years, with a wide range of applications, high selectivity, targeting traditional non-patent medicine targets, and other advantages, but there are still some areas that need to be improved, such as high molecular weight and strong molecular rigidity caused by poor oral absorption. The two PROTAC compounds created in this study (PROTAC-11 and PROTAC-12), particularly PROTAC-12, solve these problems by acceptable design and show a strong possibility of oral absorption and utilization in rat pharmacokinetic testing, which merits further preclinical investigation.