On July 11, 2024, a team of researchers led by Dr. Judith Sebolt Leopold designed a kinase inhibitor MTX-531 that can block epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-OH kinase (PI3K). The phosphoinositol 3-kinase (PI3K)/Akt pathway works downstream of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER) 2, and is associated with cell migration and survival.

BackgroundBackground

Cancer accounts for nearly one sixth of the global mortality rate. Currently, significant progress has been made in the molecular mechanisms of cancer cell signaling, and kinases play an important role in the carcinogenesis and metastasis of various types of cancer. As a key target in drug development, kinase therapy is currently the hottest research field for targeted therapy. Kinase inhibitors now account for about a quarter of current drug discovery research and development work. Single and multiple kinase inhibitors (including synthetic and natural molecules) are now targeted therapy strategies for treating human malignant tumors, and kinase therapy is influenced by adaptive resistance mechanisms. Their research team aims to design a PI3K inhibitor with high selectivity for both PI3K and EGFR. The final result showed that MTX-531 is an effective selective inhibitor of EGFR and P13K, which can target both target molecules simultaneously. It can lead to the regression of head and neck squamous cell carcinoma (HNSCC) xenografts and enhance the inhibition of PI3K mTOR or MEK (MAPK kinase) in colorectal cancer (CRC). Prior to the emergence of KRAS-G12C design, RAS had been proven to be untreatable. MTX-531 has a synergistic effect with KRAS-G12C inhibition, and P13K related inhibitors affect blood glucose, which is a common side effect. MTX-531 does not affect blood glucose in mice. Peroxisome proliferator activated receptor - γ (PPAR γ) agonists are a unique function of MTX-531. Therefore, MTX-531 is an ideal kinase inhibitor and further clinical trials are needed to validate its good preclinical toxicity characteristics.

Kinase inhibitors are enzyme inhibitors that can block the action of kinases, which help control biological processes such as cell signaling, metabolism, division, survival, and apoptosis. Some kinases are active in cancer cells, and inhibiting kinases may help prevent cancer cell growth.

The development of kinase inhibitors began in the mid-1970s. In 1978, the first oncogene was discovered to be protein kinase, followed by the discovery of cell targets for cyclosporine and the development of various protein kinase inhibitors. The field of kinase inhibitors rapidly developed. In 2001, a breakthrough was made when imatinib was approved by the FDA for the treatment of Chronic myeloid leukemia (CML). Since the initial development of imatinib, the FDA has approved 28 kinase inhibitors.

Fig. 1: Timeline depicting important events in the development and approval of kinase inhibitors over the past 20 years since imatinib was approved for treatment of CML in 2001. (Cohen, P., 2021)

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Kinase inhibitors have low toxicity and are not easily off target in targeted therapy due to their ability to effectively distinguish between normal non malignant cells and rapidly proliferating cancer cells. Drug resistance is a major challenge in targeted therapy, and kinase inhibitors can overcome resistance mechanisms, making them important for targeted therapy.

The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways regulating mammalian cell growth, survival, proliferation, and differentiation. The study of EGFR signaling pathway is very hot and has been extensively researched. In the A comprehensive pathway map of epidermal growth factor receptor signaling literature, Kanae Oda et al. constructed an EGFR signaling pathway consisting of 219 responses and 322 species (defined by the authors as an entity that takes part in reactions), which can help better understand the EGFR signaling pathway and provide important evidence for potential treatments.

The mitogen activated protein kinase (MAPK) cascade is a key signaling pathway that regulates various cellular processes, including proliferation, differentiation, apoptosis, and stress response. The MAPK pathway includes three main kinases, namely MAPK kinase, MAPK kinase, and MAPK. Extracellular signal regulated kinase 1/2 (ERK) belongs to the mitogen activated protein kinase (MAPK) family and plays a role in the signaling cascade, transmitting extracellular signals to intracellular targets. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signaling cascade among all MAPK signaling pathways and plays a crucial role in the survival and development of tumor cells. The MAPK signaling pathway plays an important role in regulating various physiological processes such as cell growth, development, division, and death. ERK is a member of the MAPK family, and the ERK/MAPK signaling pathway is the core of the signaling network involved in regulating cell growth, development, and division.

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway that plays an important role in regulating the cell cycle. Therefore, it is directly related to cell quiescence, proliferation, cancer and longevity. The phosphoinositide 3 kinase (PI3K)/Akt/mammalian (or mechanism) rapamycin target (mTOR) pathway is a complex intracellular pathway, which can lead to cell growth and tumor proliferation, and plays an important role in the endocrine resistance of breast cancer. PI3K phosphorylates phosphatidylinositide 4,5 diphosphate (PIP 2) into phosphatidylinositide 3,4,4-triphosphate (PIP 3), which leads to the phosphorylation of serine/threonine kinase Akt, thus affecting cancer cell cycle, survival and growth. mTOR is a serine/threonine kinase. Threonine protein kinase is located downstream of PI3K and Akt.

[1]https://www.technologynetworks.com/tn/news/drug-candidate-blocks-cancer-therapy-resistance-in-mouse-models-389222