Homo-PROTAC Technology Development
BOC Sciences is a leading biopharmaceutical company dedicated to the development and production of molecular drugs, especially in the field of homo-proteolysis targeting chimera (homo-PROTAC) technology, and is widely recognized for its excellence in drug development, animal testing and preclinical research. Homo-PROTAC molecules treat disease by inducing the degradation of target proteins, and this area is becoming a focus of drug development. BOC Sciences offers a comprehensive range of services from initial molecular design to preclinical studies to accelerate homo-PROTAC drug development.
What is homo-PROTAC?
Dose-related adverse reactions of MDM2-P53 inhibitors have attracted great attention in the development of clinically safe anticancer drugs, and it is necessary to develop new and more effective p53-MDM2 blocking molecules.
PROTAC is an emerging anti-tumor drug development technology, which has the advantage of low dose and efficient degradation of target proteins. However, in addition to binding the target protein, PROTAC usually introduces a second target, E3 ubiquitin ligase, which may produce inhibition or off-target effect on the second target protein when binding E3 ubiquitin ligase, resulting in related toxic side effects. Studies have shown that PROTAC designed with E3 ligand containing CRBN can degrade not only the target protein, but also other proteins at the same time, resulting in off-target effects. Homologous PROTAC is a new form of PROTAC technology, which is formed by the direct connection of two identical ligand molecules, that is, the E3 ligand (target protein ligand) exists in dimerized form to mediate the degradation of its own binding protein. Compared with traditional PROTAC molecules, the advantage of homo-PROTAC is that it does not introduce a second target, which can effectively avoid potential toxic side effects. MDM2 protein is both target protein and E3 ubiquitin ligase, which provides a theoretical basis for the design of isotype PROTAC.
Homo-PROTAC design strategy. (He, S., 2021)
Homo-PROTAC technology has broad application prospects in drug development and disease treatment. Compared with PROTAC, homo-PROTAC technology can reduce off-target effect and improve protein degradation efficiency. Homo-PROTACs can target proteins that are difficult to regulate with traditional small-molecule drug inhibitors. For example, some key oncogenic proteins, transcription factors, or protein complexes that are overexpressed or malregulated play an important role in the disease. Therefore, homo-PROTACs, by degrading these proteins, could provide a new therapeutic strategy, especially in the field of anti-cancer, showing great potential.
Homo-PROTAC development services at BOC Sciences
BOC Sciences has a comprehensive range of homo-PROTAC technology capabilities, including VHL-based homo-PROTACs, CRBN-based homo-PROTACs and IAP-based homo-PROTACs. Able to provide professional services at multiple levels, including initial design, chemical synthesis, bioactivity testing and efficacy evaluation.
Design and synthesis of homo-PROTAC
Target selection: Select the appropriate protein target according to the biological target provided by the customer. Some common targets include enzymes, transcription factors, and receptors.
Linker selection and design: The linker part of homo-PROTAC was designed to efficiently bind the target protein and E3 ubiquitin ligase. The linker part usually consists of a bridging molecule that binds the two parts together by a covalent bond.
Scenario analysis and theoretical calculation: Scenario analysis and molecular dynamics simulation are performed on the designed molecules to predict their binding energy, stability and chemical activity in the cell.
Chemical synthesis: BOC Sciences has an advanced organic synthesis laboratory that can synthesize and purify designed homo-PROTAC molecules quickly and efficiently. Its synthesis steps follow strict process standards to ensure product quality and purity.
Chemical characterization and optimization
Accurate chemical characterization was crucial in the development of homo-PROTAC. BOC Sciences used a variety of modern analytical techniques to fully characterize the synthesized homo-PROTAC molecule to ensure its correct structure, high purity and good stability.
Nuclear magnetic resonance (NMR): The structure of homo-PROTAC was analyzed by one - and two-dimensional NMR spectroscopy to confirm the details of its molecular skeleton and linker.
Mass spectrometry (MS): The use of liquid mass spectrometry and gas mass spectrometry technology to determine the molecular weight of the molecule and its fragment composition, so as to further support the molecular structure.
Infrared spectroscopy (IR) and ultraviolet spectroscopy (UV): Information about intramolecular bonding patterns and electronic structures is obtained by analyzing their infrared and ultraviolet absorption spectra.
High performance liquid chromatography (HPLC) and gas chromatography (GC): Used for purity analysis to ensure high purity and efficiency of the synthesized homo-PROTAC in the target application.
In order to achieve the best results for homo-PROTAC molecules in specific applications, BOC Sciences also provides professional optimization services.
Structural optimization: Fine-tuning of homo-PROTAC bridging molecules and ligands to improve target selectivity and degradation efficiency.
Pharmacokinetic (PK) optimization: Improve its stability and bioavailability in vivo by regulating its molecular structure and physicochemical properties.
Biological evaluation
BOC Sciences is equipped with an advanced biological evaluation platform that enables comprehensive biological function evaluation of synthetic homo-PROTAC. It includes cell and in vivo experiments to evaluate the efficiency and specificity of its degradation of target proteins.
Target protein identification and validation: Precise identification and validation of homo-PROTAC target proteins using highly sensitive mass spectrometry and proteomic methods.
Evaluation of degradation efficiency: The degradation efficiency of homo-PROTAC in vivo and in vitro was evaluated through cell experiments and animal model experiments. The time and dose response curves of protein degradation were analyzed by Western imprinting and ELISA.
Selective evaluation: Quantitative PCR and proteomics methods were used to evaluate the target selectivity of homo-PROTAC to ensure that it only degrades specific target proteins, avoiding the side effects caused by the degradation of non-target proteins.
Cytotoxicity and safety evaluation: A series of cytotoxicity tests were performed to evaluate homo-PROTAC toxicity to a variety of cell lines. In addition, animal safety experiments were carried out to verify its systemic toxicity and long-term safety.
In vivo pharmacological studies: To evaluate the mechanism of action and therapeutic effects of homo-PROTAC in vivo. These studies often involve a comparison of different doses and routes of administration to determine the best dosing regimen.
Pharmacokinetic studies: To understand the absorption, distribution, metabolism and excretion characteristics of homo-PROTAC molecules by measuring the blood concentration at different time points. These data have important guiding significance for determining dosage and frequency of administration.
Toxicological studies: Assessing the safety of homo-PROTAC molecules. Acute, subacute, and chronic toxicity tests are included to identify possible toxic reactions and safe dosage ranges.
Pharmacodynamic studies: To further confirm the biological activity and effectiveness of homo-PROTAC molecules. These studies typically use specific disease models to determine treatment effectiveness by evaluating biomarkers and pathological changes.
Advantage of our services
With its advanced technology platform and extensive research experience, BOC Sciences is able to provide customers with research and development support of homo-PROTAC throughout the entire process, from early discovery to preclinical studies. The company focuses on close cooperation with customers and regularly provides experimental progress reports and data analysis to ensure that the project progresses as planned. Whether it is an academic research team or a pharmaceutical company, BOC Sciences can provide efficient and reliable technical support of homo-PROTAC tailored to the needs of its customers.
FAQ
1. What is the difference between homo-PROTAC and conventional PROTAC?
A conventional PROTAC molecule consists of three parts: a target protein ligand, an E3 ubiquitin ligase ligand, and a linker that connects the two. In contrast, homo-PROTAC does not introduce a second target, and both of its ligands target the same E3 ligase, which can reduce off-target effects and improve drug selectivity and safety.
2. How does homo-PROTAC work?
Homo-PROTAC induces self-ubiquitination of E3 ligase by bringing two E3 ubiquitin ligase molecules closer together and promoting dimerization. Ubiquidized E3 ligases are subsequently recognized and degraded by the proteasome. In some cases, homo-PROTAC can also induce degradation of target proteins that bind to E3 ligases.
3. What are the advantages of homo-PROTAC?
- Reduced off-target effects: By not introducing additional E3 ligase as a second target, homo-PROTAC reduces the risk of non-specific protein degradation.
- Increased selectivity and safety: By specifically targeting an E3 ligase, homo-PROTAC is able to degrade the target protein more precisely, with fewer side effects.
- Improve degradation efficiency: homo-PROTAC can amplify the degradation effect and improve the degradation efficiency by promoting the self-degradation of E3 ligase.
4. How to design and synthesize homo-PROTAC?
Designing homo-PROTAC involves selecting a suitable E3 ligand, optimizing the length and chemical properties of the linker, and evaluating the bioactivity and pharmacokinetic properties of the compound. Synthesis is usually performed using a chemical synthesis method that involves multiple steps to join two ligands and linkers.
Reference:
- He, S., et al. Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer. Acta Pharmaceutica Sinica B. 2021, 11(6): 1617-1628.
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
