Sunny Fang

At present, there are two main types of protein degraders. One is PROTAC, which degrades target proteins through ubiquitin-proteasome pathway. The other type is molecular glue, which also binds ubiquitinated ligases. But unlike PROTACs, molecular glues induce protein degradation by inducing PPI between ubiquitin ligases and substrates, which can degrade non-druggable target proteins , does not require a binding pocket on the target protein.   Molecular glue refers to a class of small molecular compounds that can mediate protein-protein interaction. It can promote dimerization or co-localization of two proteins by forming ternary complexes, thus producing a variety of biological and pharmacological functions.   The Development History of Molecular Glue   The concept of molecular glue was first proposed in the early 1990s. The immunosuppressants cyclosporin A (CsA) and FK506 are the first molecular glues. Although CsA and FK506 have different direct ... Continue reading →

Currently, ADC has played a significant role in the treatment of some malignant tumors, such as trastuzumab in the treatment of breast cancer, but its therapeutic application in prostate cancer (PCa) has progressed slowly. In recent years, ADC has made rapid progress in the treatment of metastatic castration-resistant prostate cancer (mCRPC). STEAP1, TROP2, PSMA, CD46, and B7-H3 are currently being focused on as optimal antigens, and studies suggest that these antigens may be targeted by ADCs.   1 ADC for the treatment of PCa   PSMA-based ADCs   PSMA (prostate-specific membrane antigen) is a cell membrane protein specifically expressed by prostate cells, and its expression in PCa and metastatic cells is significantly higher than that in normal prostate tissue. Three PSMA-targeted ADCs are currently in clinical studies (MLN2704, PSMA-MMAE and MEDI3726).   2. Other ADCs   STEAP1 (six-segment transmembrane epithelial antigen of the prostate), an ion/protein ... Continue reading →

Antibody-drug conjugate (ADC) consists of linker, payload, and monoclonal antibody (mAb). It combines the advantages of high specific targeting ability and strong killing effect to achieve accurate and efficient killing of cancer cells, which has become one of the hot spots in the research and development of anticancer drugs. Since the first ADC drug Mylotarg (gemtuzumab ozogamicin) was approved by the FDA in 2000, 14 ADC drugs have been approved globally for hematological malignancies and solid tumors as of December 2021. In addition, There are more than 100 ADC candidates in various stages of clinical trials.   Back in the early 1900s, Paul Ehrlich first proposed the concept of the "magic bullet" and hypothesized that certain compounds could go directly into certain desired targets in cells to cure diseases. In theory, these compounds should be effective at killing cancer cells, but harmless to normal cells.   In 2000, the US Food and Drug Administration ... Continue reading →

Technological advances have re-established ADC as a viable treatment strategy for advanced solid tumors. ADCs targeting several tumor targets have shown great potential in the treatment of refractory NSCLC, including HER2, HER3, TROP2, CEACAM5, and MET. On August 11, 2022, the FDA accelerated approval of Enhertu (trastuzumab deruxtecan, T‑DXd), a HER2 ADC drug jointly developed by Astrazeneca and Daiichi Sankyo, for patients with unresectable or metastatic NSCLC with HER2 mutations. It is the first drug approved by the FDA for the treatment of HER2-mutated NSCLC, which confirms that ADC drugs have great potential for NSCLC. This article briefly introduces five potential ADC targets and representative drugs for NSCLC.   HER2   HER2 gene amplification, gene mutation and protein overexpression have been found in NSCLC. HER2 is overexpressed in nearly 20% of NSCLCS, and HER2 mutations are found in 2-4% of NSCLCS. Activating mutations in the HER2 gene promote ... Continue reading →

Since the first successful application of messenger ribonucleic acid (mRNA) as a vaccine agent in clinical studies, many advances have been made in the field of mRNA therapeutic technology after nearly 30 years of development. Vaccines are essential tools for the prevention, control and/or eradication of infectious diseases and are an essential part of global public health programmes.   The development and approval of an effective coronavirus disease 2019 (COVID-19) vaccine is an important milestone during the current pandemic. To combat the disease caused by a previously unknown pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a large number of vaccine development projects have been launched simultaneously. According to the World Health Organization's Vaccine Tracker Report, as of January 14, 2022, there are 333 vaccine candidates in development, of which 139 have entered the clinical stage.   Compared with traditional vaccines, which are ... Continue reading →

Although the treatment of type 2 diabetes (T2DM) has made impressive progress in the past few decades, researchers are constantly searching for new treatments. How to better control blood glucose and reduce diabetes-related complications has become a hot topic in the field of T2DM research.   Previously, The Lancet Diabetes Endocrinology published an in-depth review detailing novel therapeutic targets for T2DM, mechanisms of drug action, and corresponding hypoglycemic efficacy. It involves innovation with traditional insulin and a host of other new drugs in the pipeline.   Current status of treatment development of T2DM   In recent years, the prevalence of T2DM has been increasing rapidly worldwide, which has become a serious public health problem worldwide. The short-term goal of T2DM treatment is to control hyperglycemia, so hypoglycemic therapy is the main treatment for T2DM patients. In addition, healthy lifestyle intervention combined with other drugs to prevent ... Continue reading →

In the field of targeted delivery of drug conjugates, the concept of the magic bullet was proposed more than a hundred years ago. Magic bullet drugs can specifically identify and kill cancer cells without harming normal cells. With the continuous progress of protein genetic engineering, chemical conjugation and other technologies, the field of targeted delivery of drug conjugates is not limited to antibody drug conjugates, and most structures with specific targeted effects can be used as carriers of small molecule toxins. In recent years, the scope and application scenarios of drug conjugates, including multiple concepts such as combination medication and precise drug delivery, have continued to expand, and a variety of emerging conjugation technology concepts have emerged one after another.   In general, the research and development of 9 types of drug conjugates are favored by relevant institutions and enterprises.   01 Antibody Drug Conjugates (ADC)   ADC, ... Continue reading →

Since the COVID-19 epidemic, Pfizer and Moderna have used mRNA technology in a vaccine to help humans fight COVID-19. While mRNA technology is new to the public, the research has been around since the early 1990s.   What is an mRNA vaccine?   An mRNA vaccine is a vaccine that uses a molecular copy of messenger RNA (mRNA) to generate an immune response. Such vaccines deliver mRNA molecules into the body's immune cells, where they deliver a specific set of instructions to make protein fragments used by certain viruses. These protein molecules stimulate an adaptive immune response, teaching the body to recognize and destroy the corresponding viral attack. Using this technology, scientists have been experimenting with the potential use of mRNA for deadly diseases such as influenza, Ebola and SARS. Scientists have been experimenting with the use of mRNA therapy to develop personalized cancer treatments, as well as to develop vaccines against infectious diseases such as ... Continue reading →

Most of the drugs currently in clinical use are based on small molecules and use the "occupancy-driven" mode of action to inhibit the function of proteins and play a role in the treatment of diseases. Different from traditional small molecule inhibitors and antagonists, protein degradation technology has developed rapidly in recent years because of its ability to induce the degradation of therapeutic target proteins, providing a new idea for the development of new drugs. PROTACs (Proteolysis-targeting Chimeras), which was first proposed by Crews et al in 2001, can reduce protein levels rather than inhibit protein functions by taking advantage of the natural protein cleaning system in the body. PROTAC is a heterobifunctional molecule with one end connected to a ligand that binds the target protein, one end to an E3 ubiquitin ligase, and a suitable Linker in the middle. PROTAC degradation of target proteins is achieved through the ubiquitin proteasome system (UPS). Since ... Continue reading →

Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease clinically manifested by cognitive impairment, behavioral abnormalities, and social deficits. It is predicted that by 2050, the number of people 65 and older with dementia in the United States could reach 13.8 million. In China, more than 15.07 million elderly people aged 60 or over suffer from dementia, of which about 9.83 million suffer from AD. At present, the pathogenesis of AD remains unclear. β-Amyloid deposition and tau hyperphosphorylation are widely recognized as neurobiological mechanisms of AD pathogenesis. In addition, other age-related, protective, and disease-promoting factors may interact with the core mechanisms of AD and may be involved in AD pathogenesis. In recent years, the gene editing technology of CRISPR/Cas9 has developed rapidly, showing great potential in the fields of basic research and disease treatment. Recently, gene editing technology has been evaluated ... Continue reading →

In recent years, targeted protein degraders have entered the mainstream of drug development at a very rapid rate. Thalidomide and its derivatives for the treatment of multiple myeloma and other conditions have demonstrated the potential of protein degraders, while ARV-471, an estrogen receptor degrader based on the drug development of thalidomide, is targeted at the early stage of breast cancer has continued to show superior performance in clinical trials. Currently, targeted protein degradators are mainly divided into two types: small molecular "molecular glue" and biffunctional molecular degradators (PROTAC), both of which can mediate the binding and degradation of E3 ubiquitin ligase to the target protein. But the definition of the former has always been so vague that people often lump them together.  In fact, there are significant differences in the mechanism of action and thermodynamic behavior between the two. The most important difference is that the ... Continue reading →

A study conducted under the Lung Cancer Master Protocol (Lung-MAP) found that when treated with a combination of ramuzumab (Cyramza) and Keytruda,  Patients with advanced NSCLC whose cancer progressed during prior immunotherapy lived significantly longer than when treated with one of the current standard therapies for this cancer. The hazard ratio (80% confidence interval) for overall survival (OS) time for patients in the study group versus those in the standard-of-care group was 0.69 (0.51-0.92). The median OS time in the two groups was 14.5 months and 11.6 months, respectively. The results was published in the Journal of Clinical Oncology. The study, also known as S1800A, was conducted as part of Lung-MAP, the first lung cancer precision medicine trial supported by the National Cancer Institute (NCI), a division of the National Institutes of Health (NIH), and conducted at NCI’s National Clinical Trials Network (NCTN) and the NCI Community Oncology Research ... Continue reading →

Polyethylene glycol (PEG) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), it has wide variety of applications depending on the length of the polymer chain and the molecular weight of the final polymer.   The synthesis of PEG is done by polymerizing ethylene oxide, the main ingredient in antifreeze, using a ring-opening technique, which allows for PEGs of a range of molecular weights and molecular weight distributions to be constructed. This range in weights is what makes it suitable for several uses. While varying the molecular weight of PEG can have slight effects on its characteristics, mostly on its shape and physical appearance, many characteristics define PEG. It is non-toxic, colorless, inert, odorless, and non-volatile. Also, it is incredibly soluble in water, and organic solvents such as benzene, carbon tetrachloride, and ... Continue reading →

Canagliflozin is a medication used to treat type 2 diabetes. It is a third-line medication to be tried after metformin, a first-line medication for type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. Mechanism action of Canagliflozin Canagliflozin is a sodium-glucose cotransporter (SGLT2) inhibitor. Glucose filtered in the renal tubular lumen is mainly reabsorbed by SGLT2 expressed in the proximal renal tubule. By inhibiting SGLT2, cagliegin reduces the renal reabsorption of filtered glucose, lowers renal glucose threshold (RTG) and increases urine glucose excretion, thus reducing blood glucose. It is important to note that SGLT2 inhibitors are safe because their hypoglycemic effect is insulin-independent and fasting increases compensatory production of hepatic endogenous glucose. What are the effects of Canagliflozin? 1. Lower blood sugar As a new type of hypoglycemic drug, Canagliflozin has obvious advantages compared with ... Continue reading →

Numerous applications of PEGs have been reported in the scientific literature over the years. Due to their solubility in water, excellent biocompatibility and non-immunogenicity, PEG linkers are widely used in biological and medical research, such as antibody-drug conjugates, nanoparticle drug delivery, biotinylation, PEGylation protein drugs and small molecule drugs, etc. What are PEG Linkers? PEG linkers, also known as PEG reagents, are chemically functionalized PEG linkers. PEG linkers are particularly attractive as a cross-linker for conjugation and biolabeling, due to their water solubility, lack of toxicity, low immunogenicity. Monodispersed and polydispersed are two classes of PEG linkers. Monodispersed PEG has an exact number of PEG units with a specific single chemical structure with precise molecular weight. But the molecular weight of polydisperse PEG is indeterminate and distributed within a certain range. Application of PEG Linkers Long-acting drugs are the traditional ... Continue reading →

Ensitrelvir (code name S-217622, brand name Xocova),  is a new inhibitor of the SARS-CoV-2 major protease (Mpro), also known as 3C-like protease, has been shown to reduce the viral load and help alleviate the severity of SARS-CoV-2 in infected hamsters. In cells, low nanomolar to sub-micromolar doses of Ensitrelvir suppress viral growth. In hamsters, oral treatment of Ensitrelvir showed excellent pharmacokinetic qualities and hastened recovery from acute SARS-CoV-2 infection.   Ensitrelvir also demonstrated antiviral effectiveness against SARS-CoV-2 variants of concern (VOCs), such as the highly pathogenic Delta variant and the newly discovered Omicron variant. Overall, these findings show that Ensitrelvir, which is an antiviral drug that is currently being tested in Phase II/III clinical trials, has impressive antiviral efficiency and effectiveness against SARS-CoV-2 and could be a viable oral treatment option for COVID-19.   The mechanism of action of Ensitrelvir ... Continue reading →

Just one dose of a new nanoparticle-based COVID-19 vaccine is enough to generate an immune response in animals, and the vaccines currently in clinical use are on track. With minor changes, Northwestern University researchers hope the same vaccine platform could target other infectious diseases. In a new study, mice that received protein-based immunizations survived 100% when challenged with a lethal dose of the SARS-CoV-2 virus, which causes COVID-19. None of the mice developed lung damage due to SARS-CoV-2 exposure. All mice that did not receive the nanoparticle vaccine died during the 14-day trial. The findings, published this week in the Proceedings of the National Academy of Sciences, outline the structure-function relationship between the first spherical nucleic acid (SNA) vaccine developed to prevent viral infection. The nanoparticles, known as SNAs, house immune targets, globular DNA that can enter and stimulate immune cells with extremely high efficiency. SNAs have been ... Continue reading →

On February 16, 2022, the data on Paxlovid previously published by Pfizer and submitted to the FDA were published in the New England Journal of Medicine (NEJM). This NEJM article published viral load data that Paxlovid reduced viral load by 0.868 log10 compared to controls for 5 days of treatment, which equates to a remarkable 7.38-fold reduction in viral load. This pivotal study (NCT04960202) enrolled 2,246 patients with COVID-19 , 1,120 received Paxlovid and 1,126 received placebo. Interim analysis showed that 28 days after receiving treatment, Paxlovid reduced the risk of hospitalization and death by 89.1% (p <0.001). Applying the final results of the ITT analysis, Paxlovid reduced the risk of hospitalization and death by 88.9% (p <0.001). “Paxlovid is the potencial blockbuster drugs for COVID-19 treatment. And in response to this trend, our management decides to introduce a new product line, providing Paxlovid intermediates caronic anhydride & derivatives ... Continue reading →

Among adults with overweight or obesity, once-weekly subcutaneous semaglutide plus counseling for diet and physical activity results in significantly greater weight loss at 68 weeks than once-daily subcutaneous liraglutide, according to a study published in the Jan. 11 issue of the Journal of the American Medical Association. Domenica M. Rubino, M.D., from the Washington Center for Weight Management and Research in Arlington, Virginia, and colleagues compared the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide (126 patients) versus once-daily subcutaneous liraglutide (127 patients) or placebo (85 patients) in people with overweight or obesity also undertaking diet and physical activity and followed for 68 weeks. The researchers found that participants had significantly greater odds of achieving ≥10 percent, ≥15 percent, and ≥20 percent weight loss with semaglutide versus liraglutide (odds ratios, 6.3, 7.9, and 8.2, respectively). Discontinuation of ... Continue reading →

According to statistics from the World Health Organization (WHO), nearly 2 billion people are overweight or obese worldwide. Every year, overweight or obesity causes 2.8 million deaths.     What 's Orlistat ?    Orlistat is a lipase inhibitor used in the treatment of obesity that works by inhibiting fat-metabolizing enzymes. It was originally approved by the FDA in 1999 as the prescription drug Exenical, was approved in 2007 as the over-the-counter medication Alli. This drug is a generally well-tolerated and effective weight-loss aid.   What 's the mechanism of action?   Orlistat is a drug designed to treat obesity. It'sa potent and selective inhibitor of various lipase enzymes responsible for the metabolism of fat. It acts in the gastrointestinal (GI) tract via covalent binding to the serine residues located on the active site of both When orlistat is taken with food containing fat, it partially ... Continue reading →