GT-20029

Proteolysis Targeting Chimeras (PROTACs) technology is a new protein degradation strategy that has emerged in recent years. It utilizes bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin-proteasome system. PROTACs can not only serve as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but can also provide unique tools for biological research in a catalytic, reversible, and rapid manner. Advantages of PROTACs1. Wider targeting range:  Traditional small molecules and antibodies are all act on diseases through an "occupancy-driven" model by inhibiting the functions of target proteins. This functioning model requires either high concentrations of inhibitors or monoclonal antibodies to occupy the target's active sites and thus block the transduction of downstream signalling pathways. In contrast, PROTACs are "event-driven", and instead of affecting the protein's function, they mediate the degradation of disease-causing target proteins. As long as PROTACs induce the formation of a ternary complex and ubiquitinate the target protein, it can theoretically be used cyclically and repetitively, thus even small catalytic amounts can have an effect. Moreover, PROTACs can significantly broaden the range of targets, as they can induce protein degradation through binding alone, even when the protein has no active sites (e.g. scaffold proteins). Targets suitable for PROTACs typically have four characteristics:  i) "Undruggable";  ii) Abnormal protein expression (including overexpression, mutation, abnormal aggregation, misfolding, etc.);  iii) Scaffold proteins;  iv) Resistant to existing therapies and drugs. 2. Higher selectivity and safety:  In comparison to traditional small molecule inhibitors, PROTACs can achieve levels of selectivity that are difficult for small molecules at some targets. As is widely known, small molecule inhibitors often target multiple sites, for example, kinase inhibitors often use 2,4-diaminopyrimidine as a scaffold, which is used in the inhibitors of EGFR, ALK, CDK, Jak, etc. Typically, these drug molecules have poor target selectivity, and often exhibit strong inhibitory activity on various other kinases. Off-target effects often become the main source of toxicity and side effects in drug development, affecting the success rate of new drug development. 3. Overcoming resistance:  In clinical practice, it is inevitable that acquired resistance will occur with the use of small molecule inhibitors or antagonists. For instance, instances of resistance like EGFR-T790M and C797S. Although this issue of resistance can be addressed by developing new generations of inhibitors, like third and fourth generation EGFR inhibitors, new resistances will come up with the use of new generation drugs. PROTAC technology has already shown some advantages in overcoming resistance. Several research groups around the world are trying to use PROTACs for EGFR, hoping to overcome drug-resistant mutations or explore breakthrough protein degradation therapies for inhibitors. Studies have shown that the first, second, third, and fourth generation inhibitors, as ligands binding target protein EGFR, have all been applied in PROTAC design. In terms of antiviral actions, PROTACs also have a role to play. The feasibility of antiviral PROTACs molecules was initially established in research into the degradation of Hepatitis C virus (HCV) NS3/4A protease. Over the past two decades, PROTACs technology has gradually developed into one of the hottest techniques in modern drug research, attracting extensive attention from research institutions, pharmaceutical companies, and investors. The most advanced PROTACs drug is still in Phase II clinical trials and the pioneers will have to deal with a host of issues in pharmacology, toxicology, biochemical characteristics, and even commercialization. Compared to popular fields (cell gene therapy, large molecule drugs), PROTACs still has a great deal of room for development. PROTACs Competitive LandscapeAccording to Patsnap Synapse, as of 24 Sep 2023, there are a total of 359 PROTACs drugs worldwide, from 166 organizations, covering 125 targets, 83 indications, and conducting 71 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications,  targets, organizations, clinical trials, and clinical results related to this drug type. Phase III Clinical Trial of saRNA Medicinal: VepdegestrantVepdegestrant is a drug classified as PROTACs, which stands for Proteolysis Targeting Chimeras. This type of drug works by utilizing small molecules to target specific proteins for degradation within cells. In the case of Vepdegestrant, its target is ERα, which is a protein involved in estrogen receptor signaling. The therapeutic areas for Vepdegestrant include neoplasms, which refers to abnormal growth of cells that can lead to cancer, as well as skin and musculoskeletal diseases. This suggests that the drug may have potential applications in treating various types of cancers, as well as conditions affecting the skin and musculoskeletal system. The active indication for Vepdegestrant is advanced breast cancer, specifically ER-positive/HER2-negative breast cancer. This indicates that the drug is intended for use in patients with breast cancer that has spread to other parts of the body and is characterized by the presence of estrogen receptors but the absence of HER2 receptors. Vepdegestrant was developed by Arvinas, Inc., an originator organization in the pharmaceutical industry. The drug has reached the phase 3 of clinical development. Phase 3 trials are large-scale studies conducted to evaluate the safety and efficacy of a drug in a larger patient population before it can be submitted for regulatory approval. In summary, Vepdegestrant is a PROTACs drug that targets ERα and is being developed by Arvinas, Inc. It has shown potential in the treatment of advanced breast cancer, specifically ER-positive/HER2-negative breast cancer. The drug is currently in Phase 3 clinical trials, indicating that it has progressed through earlier stages of development and is being evaluated in larger patient populations. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. Phase II Clinical Trial of saRNA Medicinal: GT20029The drug GT20029 is a type of PROTACs, which stands for Proteolysis Targeting Chimeras. PROTACs are a new class of drugs that work by harnessing the body's own protein degradation system to selectively remove disease-causing proteins. In the case of GT20029, it targets the androgen receptor (AR), which is involved in the development and progression of various skin and musculoskeletal diseases. The therapeutic areas for GT20029 are focused on skin and musculoskeletal diseases. Specifically, it is being developed for the treatment of androgenetic alopecia, which is a common form of hair loss that affects both men and women, and acne vulgaris, a chronic inflammatory skin condition characterized by pimples, blackheads, and whiteheads. The drug GT20029 is being developed by Suzhou Kintor Pharmaceuticals, Inc., an originator organization based in China. It has reached the phase 2 of clinical development. Phase 2 trials involve a larger number of patients and aim to further evaluate the safety and efficacy of the drug in the target population. Based on the available information, GT20029 shows promise in the treatment of androgenetic alopecia and acne vulgaris. The use of PROTACs as a novel therapeutic approach offers the potential for more targeted and effective treatments for these conditions. However, further clinical trials and research are needed to fully assess the safety and efficacy of GT20029. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. In summary, GT20029 is a PROTACs drug being developed by Suzhou Kintor Pharmaceuticals, Inc. It targets the androgen receptor and is intended for the treatment of androgenetic alopecia and acne vulgaris. The drug has reached Phase 2 of clinical development. Further research and trials are required to determine its full potential in treating these skin and musculoskeletal diseases.

Due to their large molecular weight (700-1200Da), poor solubility, and low permeability, PROTAC molecules generally have a low oral bioavailability (F). Therefore, researchers often go to great lengths to increase F, such as optimizing the linker to improve permeability and metabolic stability, selecting E3 ligase ligands with smaller molecular weights, and using prodrug strategies, etc. The structure and bioavailability in various species of ARD-1676The research group of Wang Shaomeng recently published a paper in JMC, reporting the discovery of ARD-1676 and characterizing its preclinical properties. ARD-1676 is an orally effective PROTAC androgen receptor (AR) degrader. The paper mentions that the DC50 values of ARD-1676 in AR+ VCaP and LNCaP cell lines are 0.1 and 1.1 nM respectively, and the IC50 values in VCaP and LNCaP cell lines are 11.5 and 2.8 nM respectively.  👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. ARD-1676 can effectively induce the degradation of a series of clinically relevant AR mutants. The oral bioavailability of ARD-1676 in mice, rats, dogs, and monkeys is 67%, 44%, 31%, and 99% respectively. Oral administration of ARD-1676 can effectively reduce the AR protein levels in mouse VCaP tumor tissues and inhibit tumor growth in a VCaP mouse xenograft tumor model, with no signs of toxicity.  The oral bioavailability in monkeys is 99%, which is relatively rare among PROTAC molecules. The ADME Characteristics of ARD-1676ARD-1676 has lower passive cell permeability, with Papp A-B not reaching 1×10-6, and an efflux ratio of 1.8, suggesting a low potential as a substrate for P-glycoprotein (Pgp). The study evaluated the stability of ARD-1676 in the liver microsomes, hepatocytes, and plasma in mice, rats, dogs, non-human primates (NHP), and humans. It was concluded that the compound demonstrated good stability in the microsome, hepatocytes, and plasma from all five species. The ADME and hERG inhibition data of ARD-1676.The study also evaluated ARD-1676 for its inhibitory effect on all major cytochrome P450 (CYP) subtypes and found that ARD-1676 had no inhibitory effect on the evaluated CYP subtypes. The potential inhibitory effect of ARD-1676 on hERG in vitro was also assessed. Compared to the control group, the inhibitory effect of ARD-1676 under 3 and 30 μM was negligible, suggesting that ARD-1676 does not have a hERG toxicity trend. The PK parameters of ARD-1676 in mice, rats, dogs, and monkeysThe figure above shows the pharmacokinetic parameters of ARD-1676 in mice, rats, dogs, and monkeys. In mice, ARD-1676 has a very low clearance rate (Cl = 0.04 L/h/kg), a moderate volume of distribution (Vss = 0.23 L/kg), and a T1/2 of 4.3-4.4 h for both intravenous and oral administration. With a dose of 5 mg/kg, the Cmax = 9124 ng/mL, AUC = 85243 h·ng/mL, and the oral bioavailability is 67%. In dogs, ARD-1676 has a low clearance rate (Cl = 0.19 L/h/kg), a moderate volume of distribution (Vss = 1.7 L/kg), an intravenous T1/2 of 9.9 h, an oral T1/2 of 27.4 h, a Cmax of 1031 ng/mL for oral administration, and an AUC = 15170 h·ng/mL. The oral bioavailability is 31%. In monkeys, ARD-1676 has a low clearance (Cl = 0.2 L/h/kg), a moderate volume of distribution (Vss = 2.1 L/kg), and a T1/2 of 9.6 ~ 9.9 h for both intravenous and oral administration. With a dose of 2mg /kg, the Cmax = 1520 ng/mL, AUC = 10302 h·ng/mL, and the oral bioavailability is 99%. It is worth noting that the solvents used across the four species are different, which can greatly impact bioavailability. The Pharmacokinetics and Antitumor Effect of ARD-1676 in MiceA single oral dose of 12.5 mg/kg of ARD-1676 was administered to mice with VCaP xenograft tumors. The immunoblot analysis of tumor tissues showed that ARD-1676 effectively decreased the level of AR proteins by 96% and 93% at the 6 h and 24 h time points, respectively. According to the pharmacodynamic data of ARD-1676, its antitumor activity was determined in the VCaP xenograft tumor model in mice, yielding the data graphically represented below. The pharmacokinetics data indicated that ARD-1676 effectively and dose-dependently inhibited tumor growth under all 3 assessed doses. Anti-tumor activity of ARD-1676 in SCID mice VCaP xenograft modelARD-2051 and ARD-1676In June this year, the team led by Wang Shaomeng also reported the discovery of ARD-2051. As shown in the figure below, the oral bioavailability of ARD-2051 is relatively high in small animals, but not enough in large animals. From the comparison of 27 and 30, it can be seen that the chiral methyl on the cyclobutene ring has a very significant impact on the degradation efficiency. Furthermore, the synthesis of this chiral methyl is challenging, which requires the opening and reclosing of substituted epoxide into 5-membered ring. The linker was further optimized to obtain ARD-1676. The Discovery and Synthesis of ARD-2051Progress in the Development of AR Targeting PROTAC Drugs In the Synapse database, 23 drugs were found when searching for AR and PROTAC, involving 31 development statuses, as shown in the above figure, numerous pharmaceutical companies are participating in this heated competition. Among them, GT20029 from Suzhou Kintor Pharmaceuticals is at Phase II of clinical trials, is being studied for indications such as androgenic alopecia and acne vulgaris; Arvinas' ARV-766 and ARV-110 are both in Phase I/II, with indications under research being metastatic hormone-refractory prostate cancer; Accutar Biotechnology's AC-0176, Hinova Pharmaceuticals' HP-518, and Haisco Pharmaceutical's HSK-38008 are all undergoing Phase I clinical trials, and the indications under study are castration-resistant prostate cancer and prostate cancer. The bioavailability of PROTACsThe bioavailability of PROTACs is generally poor. Lipinski's Rule of Five (Ro5) is an empirical rule that sets several criteria for drug bioavailability, typically used to predict the bioavailability of compounds. With the advent of small molecule PROTACs, the molecular weight of PROTACs has been reduced, but the hetero-bifunctional structure of PROTACs results in their violation of Ro5, leading to poor bioavailability. Permeability tests have shown that most PROTAC molecules have poor cellular permeability, thus, to date, most in vivo studies have adopted parenteral administration. Lipinski's Rule of FiveAs of 2017, approximately 6% of orally administered drugs were not within the Rule of 5 (Ro5) scope. For example, many macrocycles can be given orally, even though they clearly exist within the “beyond Rule of 5 (bRo5)” chemical space. This could be explained by their chameleon-like conformational flexibility, which promotes intestinal absorption of drugs. Pharmaceutical companies and research institutions are developing oral PROTACs, urgently requiring reasonable design standards to endow PROTACs with oral effectiveness. A study on the relationship between physicochemical properties and permeability conducted by Lokey and his colleagues has found that, even in PROTACs with almost the same molecular weight, the same ALogP, and the same number of hydrogen bond donors/acceptors, cell permeability could differ by a factor of 10. Moreover, reducing the number of hydrogen bond donors/acceptors usually improves the bioavailability of small molecules, but in the case of PROTACs, it may result in worse solubility. One milestone study by the Lokey group has showed the effectiveness of using intramolecular hydrogen bonds to mask hydrogen bond donors/acceptors, based on the aforementioned conformational flexibility. However, the rational design of such compounds with intramolecular hydrogen bonds is highly challenging. SummaryAndrogen receptors (AR) and AR signaling play a crucial role in the initiation and progression of human prostate cancer. AR-targeted therapeutic drugs, including abiraterone which inhibits androgen synthesis, and second-generation AR antagonists like enzalutamide, apalutamide and darolutamide, have been developed for the treatment of advanced human prostate cancer. Even though these drugs have proved to be effective in clinical practice, resistance to them develops within 18 months. Key resistance mechanisms include AR gene amplification, activating AR mutations, and expressions of AR variants. In most human prostate cancers resistant to AR-targeted drugs, AR and AR signaling continue to feature in tumor progression, prompting the search for new therapeutic strategies targeting AR and AR signaling. An appealing new strategy is to target AR through induced degradation of target proteins. Inspired by the clinical success of selective estrogen receptor degraders (SERDs) in the treatment of human breast cancer, selective AR degraders (SARDs) are under investigation. However, the degradation capacity of current SARD molecules is relatively weak and needs significant improvement. A second method to induce AR protein degradation is the use of PROTAC technology. PROTAC drugs include a ligand that binds to the target protein, a ligand that binds to and recruits the E3 ligase or E3 ligase complex, and a linker that connects them. The first AR PROTAC molecule was designed using bicalutamide derivatives as the AR ligand and MDM2 inhibitors as the E3 ligase ligand. With companies like Arvinas and various academic institutions continually advancing PROTAC technology, it is hoped that this kind of drug will be introduced to the market as early as possible to overcome drug resistance, thus enriching options for patients' medication. References 1.Shaomeng Wang et.al; Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer.https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jmedchem.3c01264. 2.Shaomeng Wang et.al; Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer.J. Med. Chem. 2023, 66, 8822−8843. 3.Minoru Ishikawa et.al; In vivo synthetic chemistry of proteolysis targeting chimeras (PROTACs).Bioorg. Med. Chem. 41 (2021) 116221.