Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Rapid health technology assessment of Aidi injection combined with first-line chemotherapy for non-small cell lung cancer / 中国药房

OBJECTIVE To evaluate the effectiveness， safety and economics of Aidi injection combined with first-line chemotherapy for non-small cell lung cancer （NSCLC）， and to provide evidence-based reference for clinical drug use and decision. METHODS Retrieved from PubMed， Embase， the Cochrane Library， CNKI， Wanfang databases， VIP and Health Technology Assessment （HTA） related websites， HTA reports， systematic evaluation/meta-analysis and economic evaluations about Aidi injection combined with first-line chemotherapy for NSCLC were collected from the inception to Aug. 2022. After data extraction and quality evaluation， descriptive analysis was performed for the results of included studies. RESULTS A total of 16 pieces of literature were included， involving 1 piece of systematic review， 13 pieces of meta-analysis， 2 pieces of pharmacoeconomic studies. Compared with first-line chemotherapy， Aidi injection combined with first-line chemotherapy could improve response rate and disease control rate， prolonged survival time， improved survival quality， reduced the incidence of nausea and vomiting， leukocytopenia and thrombocytopenia， and improved immune function， but had controversial effects on liver and kidney function. With the payment threshold set by 3 times the national per capita GDP in 2019， Aidi injection combined with first-line chemotherapy had a more economical probability. CONCLUSIONS Aidi injection combined with first-line chemotherapy for NSCLC has good efficacy and safety， and has certain economic benefits. However， given the limited pharmacoeconomic studies included， the economic conclusions obtained need to be carefully interpreted.

PI3K/Akt/mTOR signaling pathway in cutaneous squamous cell carcinoma / 中华皮肤科杂志

The pathogenesis of cutaneous squamous cell carcinoma (cSCC) is complicated, and treatment methods of advanced cSCC remain insufficient. This review summarizes the role of phosphatidylinositol 3-kinase (PI3K) /protein kinase B (Akt) /mammalian target of rapamycin (mTOR) signaling pathway in the pathogenesis of cSCC, as well as progress in the treatment of cSCC targeting this pathway, and provides new ideas for targeted therapy of cSCC.

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 (

Correlation of invasive central arterial pressure with peripheral arterial pressure and coronary sclerosis / 中华老年医学杂志

Objective To study the consistency among non-invasive and invasive brachial artery pressure,radial artery pressure and invasive central arterial pressure,and to explore the correlation between the severe degree of coronary artery disease and invasive central aortic pressure.Methods A total of 331 patients who underwent coronary angiography in our hospital were selected.The invasive central aortic pressure,invasive and non-invasive brachial arterial pressure,radial artery pressure in all patients were measured.The severe degrees of atherosclerosis were recorded.The differences among invasive brachial arterial pressure and invasive radial artery pressure,non-invasive brachial artery pressure and non-radial artery pressure and invasive central aortic pressure were compared.Results The systolic pressure values measured in invasive and non-invasive brachial artery and radial artery were higher than that measured by central aortic pressure,while the diastolic pressure values measured in the four peripheral artery were lower than that measured in central aorta.The pressure values measured by non-invasive brachial artery pressure were more close to that measured by invasive central aortic pressure (P＞0.05).The systolic pressure was increased and the diastolic pressure was reduced in central aortic pressure with the coronary vessel lession numbers increased.The values of systolic pressure in patients with single-vessel,double-vessel and triple-vessel lesions were (118.2± 19.5) mm Hg,(124.9 ± 19.7) mm Hg and (137.7 ± 20.6) mm Hg,respectively and the values of diastolic pressure were (86.8±8.4) mm Hg,(85.3± 10.3) mm Hg and (83.1± 9.4) mm Hg,respectively.There were significant differences in systolic and diastolic pressure values among patients with single-vessel lesions,double vessel lesions and triple-vessel lesions(F=3.93,4.31,both P＜ 0.05).Conclusions The blood pressure values measured by noninvasive brachial artery pressure are more close to that measured by invasive central aortic pressure.There is a significant correlation between the severe degree of coronary heart disease and invasive central aortic pressure.Non invasive brachial artery pressure can be used in the early detection of cardiovascular dysfunction.