Enzyme-Catalyzed Responsive Pro-PROTAC
The researchers concentrated on the distinction between the tumor microenvironment and the normal cell environment and incorporated the endogenous enzyme response chemistry of tumor cell characteristics into the molecular design of Pro-PROTAC.
- Folate receptor response: folate receptor alpha (FOLR1)
FOLR1 is a class of essential transport receptors that are highly expressed in cancer cells and can facilitate the entry of medicines into cancer cells, whereas FOLR1 is seldom or not expressed in normal tissues or cells. FOLR1-targeting technique is widely utilized in tumor imaging and targeted tumor drug delivery, allowing for extremely selective molecular drug delivery.
The Wenyi Wei team at Harvard Medical School and the Jian Jin team from Mount Icahn Medical School in Sinai published folic acid-PROTAC in 2021. The authors joined folic acid to the PROTAC molecule, which can be preferentially identified and delivered to cancer cells that show high levels of folate receptor FOLR1. Folic acid-PROTAC will be digested in cancer cells to release folic acid. After folic acid protector is removed, the PROTAC molecule will regain its targeted degradation activity and destroy the target protein successfully.
- Anoxic microenvironment response: nitroreductase (NTR)
In the case of overexpression of NTR in tumor tissues, nitroimidazole, as a substrate of NTR enzyme, can be selectively removed by enzyme catalysis, which is an important chemical group in most prodrug design.
(1) In 2021, Zhang Xiaojian’s team of Zhengzhou University focused on the anoxic environment of tumor tissue, introduced hypoxia conditioned response molecular motifs into the molecular ligands of recruitment target proteins, developed Ha-PROTAC molecules activated under hypoxia conditions, and achieved the functional activation of inert PROTAC molecules under hypoxia stimulation in tumor microenvironment.
(2) In 2022, Professor Xu Yungen and Professor Zhu Qihua of China Pharmaceutical University also reported on the PROTAC design of hypoxia response, which included the incorporation of nitroimidazole structural components into the molecular ligand portion of recruiting E3 ligase. The inclusion of cage groups into E3 ligase ligands by NTR-responsive PROTAC can boost the likelihood of PROTAC contacting different target proteins compared to the design of Ha-PROTAC.
- Redox microenvironment: NAD (P) H dehydrogenase 1 (NQO1)
Overexpression of NQO1 is strongly associated with the onset and progression of cancer. The enzyme is capable of catalyzing the dielectronic reduction of quinones in their normal physiological context, which is a crucial detoxification pathway in mammals.
In 2022, Wang Ming Research Group of Institute of Chemistry, Chinese Academy of Sciences designed two types of enzyme-responsive Pro-PROTAC molecules (NQO1-PROTAC and ROS-PROTAC) based on the catalytic activity of NQO1 overexpressed by cancer cells, to solve the scientific problem of low cell selectivity of PROTAC molecules. The authors identified the enzyme in the tumor microenvironment responsible for activating the inactive Pro-PROTAC molecule in response to chemical circumstances and exploited the overexpressed protease NQO1 in cancer cells to regulate the internal activity of PROTAC.
Radiation response of Pro-PROTAC
X-ray is a crucial component of cancer radiation therapy. Local X-ray therapy can lead to DNA damage, apoptosis and tumor necrosis. In addition, X-rays can also produce chemical reaction products such as hydrogen free radicals and hydroxyl radicals, which have been used to design prodrug activation strategies for chemotherapeutic drugs.
In 2022, Li Jinghong’s research team at Tsinghua University incorporated an azidophenyl cage group with X-ray reaction into the design of PROTAC molecules and synthesized the first RT-PROTAC with X-ray response. Due to the great spatial and temporal resolution and high tissue penetration ability of X-rays, RT-PROTAC remains inactive before to X-ray radiation and can be triggered in specific tumor tissues after X-ray radiation to prevent tumor growth in vivo.