Lysosome‐targeting chimeras (LYTACs) are an emerging therapeutic modality that effectively degrade cancer cell membranes and extracellular target proteins. In this study, a nanosphere‐based LYTAC degradation system is developed. The amphiphilic peptide‐modified N‐acetylgalactosamine (GalNAc) can self‐assemble into nanospheres with a strong affinity for asialoglycoprotein receptor targets. They can degrade different membranes and extracellular proteins by linking with the relevant antibodies. CD24, a heavily glycosylated glycosylphosphatidylinositol‐anchored surface protein, interacts with Siglec‐10 to modulate the tumor immune response. The novel Nanosphere‐AntiCD24, synthesized by linking nanospheres with CD24 antibody, accurately regulates the degradation of CD24 protein and partially restores the phagocytic function of macrophages toward tumor cells by blocking the CD24/Siglec‐10 signaling pathway. When Nanosphere‐AntiCD24 is combined with glucose oxidase, an enzyme promoting the oxidative decomposition of glucose, the combination not only effectively restores the function of macrophages in vitro but also suppresses tumor growth in xenograft mouse models without detectable toxicity to normal tissues. The results indicate that GalNAc‐modified nanospheres, as a part of LYTACs, can be successfully internalized and are an effective drug‐loading platform and a modular degradation strategy for the lysosomal degradation of cell membrane and extracellular proteins, which can be broadly applied in the fields of biochemistry and tumor therapeutics.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202300288

Nano‐LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec‐10 Signaling Pathway

Ugi reaction-assisted assembly of covalent PROTACs against glutathione peroxidase 4

Angiogenesis, the formation of new blood vessels from the existing vasculature, is pivotal in the migration, growth, and differentiation of endothelial cells in normal physiological conditions. In various types of tumour microenvironments, dysregulated angiogenesis plays a crucial role in supplying oxygen and nutrients to cancerous cells, leading to tumour size growth. VEGFR-2 tyrosine kinase has been extensively studied as a critical regulator of angiogenesis; thus, inhibition of VEGFR-2 has been widely used for cancer treatments in recent years. Quinazoline nucleus is a privileged and versatile scaffold with a broad range of pharmacological activity, especially in the field of tyrosine kinase inhibitors with more than twenty small molecule inhibitors approved by the US Food and Drug Administration in the last two decades. As of now, the U.S. FDA has approved eleven small chemical inhibitors of VEGFR-2 for various types of malignancies, with a prime example being vandetanib, a quinazoline derivative, which is a multi targeted kinase inhibitor used for the treatment of late-stage medullary thyroid cancer. Despite of prosperous discovery and development of VEGFR-2 down regulator drugs, there still exists limitations in clinical efficacy, adverse effects, a high rate of clinical discontinuation and drug resistance. Therefore, there is an urgent need for the design and synthesis of more selective and effective inhibitors to tackle these challenges. Through the gathering of this review, we have strived to broaden the extent of our view over the entire scope of quinazoline-based VEGFR-2 inhibitors. Herein, we give an overview of the importance and advancement status of reported structures, highlighting the SAR, biological evaluations and their binding modes. 

Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies.

The development of EGFR small-molecule inhibitors has provided significant benefit for the affected patient population. Unfortunately, current inhibitors are no curative therapy, and their development has been driven by on-target mutations that interfere with binding and thus inhibitory activity. Genomic studies have revealed that, in addition to these on-target mutations, there are also multiple off-target mechanisms of EGFR inhibitor resistance and novel therapeutics that can overcome these challenges are sought. Resistance to competitive 1st-generation and covalent 2nd- and 3rd-generation EGFR inhibitors is overall more complex than initially thought, and novel 4th-generation allosteric inhibitors are expected to suffer from a similar fate. Additional nongenetic mechanisms of resistance are significant and can include up to 50% of the escape pathways. These potential targets have gained recent interest and are usually not part of cancer panels that look for alterations in resistant patient specimen. We discuss the duality between genetic and nongenetic EGFR inhibitor drug resistance and summarize current team medicine approaches, wherein clinical developments, hand in hand with drug development research, drive potential opportunities for combination therapy.

/pdf/a-closer-look-at-egfr-inhibitor-resistance-in-non-small-cell-1zzse5d0.pdf

A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine

The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events

Epidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting Chimeras (PROTACs) and LYsosome Targeting Chimeras (LYTACs), take advantages of protein destruction mechanism in cells, which make up for shortcomings of traditional small molecular occupancy-driven inhibitors. PROTACs based heterobifunctional EGFR degraders were recently developed by making use of wild-type (WT) and mutated EGFR inhibitors. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the inhibitors that have been developed against WT/mutated EGFR, and then mainly focuses on the recent advances of EGFR-targeting degraders along with its limitations and unlimited prospects. 

Recent advances in the development of EGFR degraders: PROTACs and LYTACs.

Bile acids (BAs) are physiological detergents that can not only promote the digestion and absorption of lipids, but also may be a potential carcinogen. The accumulation of BAs in the body can lead to cholestatic liver cirrhosis and even liver cancer. Recently, studies demonstrated that BAs are highly accumulated in metastatic lymph nodes, but not in normal healthy lymph nodes or primary tumors. Lymph node metastasis is second only to hematogenous metastasis in liver cancer metastasis, and the survival and prognosis of hepatocellular carcinoma (HCC) patients with lymph node metastasis are significantly worse than those without lymph node metastasis. Meanwhile, component of BAs was found to significantly enhance the invasive potential of HCC cells. However, it is still poorly understood how deregulated BAs fuel the metastasis process of liver cancer. The tumor microenvironment is a complex cellular ecosystem that evolves with and supports tumor cells during their malignant transformation and metastasis progression. Aberrant BAs metabolism were found to modulate tumor immune microenvironment by preventing natural killer T (NKT) cells recruitment and increasing M2-like tumor-associated macrophages (TAMs) polarization, thus facilitate tumor immune escape and HCC development. Based on these available evidence, we hypothesize that a combination of genetic and epigenetic factors in cancerous liver tissue inhibits the uptake and stimulates the synthesis of BAs by the liver, and excess BAs further promote liver carcinogenesis and HCC metastasis by inducing immunosuppressive microenvironment.

/pdf/deregulated-bile-acids-may-drive-hepatocellular-carcinoma-2vxqqb74.pdf

Hao Ren

Papers

Recent advances in the development of EGFR degraders: PROTACs and LYTACs.

Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment