218 ՀԱՅԱՍՏԱՆԻ ԳԻՏՈՒԹՅՈՒՆՆԵՐԻ ԱԶԳԱՅԻՆ ԱԿԱԴԵՄԻԱ НАЦИОНАЛЬНАЯ АКАДЕМИЯ НАУК АРМЕНИИ NATIONAL ACADEMY OF SCIENCES OF ARMENIA ДОКЛАДЫ ԶԵԿՈԻՅՑՆԵՐ REPORTS BIOTECHNOLOGY УДК 579 DOI: 10.54503/0321-1339-2022.122.3-218 Foreign member of NAS RA V. A. Sakanyan 1 , M. A. Iradyan 2 , N. S. Iradyan 2 Development of Targeted EGFR Degradation for Cancer Treatment (Submitted 31/V 2022) Keywords: cancer therapy, EGFR, allosteric degraders, Bim phosphorylation, glutamine, anoïkis. Introduction. The main distinguishing hallmarks of cancer are self- sustaining growth signals, insensitivity to growth inhibition signals, tissue invasion and metastasis, unlimited ability to replicate, and prevention of cell death [1]. In the fight against cancer, two main principles of small molecule therapy have been developed: standard therapy and targeted therapy. Standard chemotherapeutic agents are cytotoxic because they kill cancer cells, while targeted chemotherapeutic agents are often cytostatic because they bind to tumor cells and block cell proliferation. Targeted cancer treatment requires reliable information about human genes and proteins; therefore, it became the cornerstone of precision medicine for almost three decades. Transmembrane receptor tyrosine kinases (RTKs) control various signaling pathways that play a pivotal role in the regulation of cell proliferation, motility, survival, and cell death [2]. Mutations that disrupt the functions of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) are often associated with the onset and progression of cancer (Fig. 1). Target- specific small molecules and neutralizing antibodies have been designed to inhibit proliferative phosphorylation in signaling pathways triggered by RTKs in cancer cells. Targeting the ATP binding site in RTK is an important issue in medicinal chemistry for the treatment of EGFR-associated cancer [3]. Tyrosine kinase inhibitors (TKIs) with reversible and irreversible mechanisms of action have been developed to inhibit the catalytic site, improving patient survival compared to platinum-based chemotherapy, the previous standard of care [4]. Հատոր Том Volume 122 2022 № 3