Overview
TY-1091 is a highly potent and selective new generation of Rearranged during transfection(RET) inhibitor, independently developed by TYK Medicines, Inc. Preclinical studies showed that TY-1091 strongly inhibited kinases with RET mutants, such as RET V804L, RET V804M, RET M918T, etc., as well as solvent-front mutations (G810S single mutation and double mutation), which are identified as mechanisms of acquired resistance. TY-1091 is a potent inhibitor that has potential as a treatment for multiple types of tumors carrying active RET alteration. It is intended for clinical studies in the treatment of RET fusion non-small cell lung cancer, RET mutant medullary thyroid cancer, and other RET altered solid tumors. Currently, the phase I/II dose-escalation and dose-extension study is being conducted in China.
Mechanism of Action
The proto-oncogene rearranged during transfection (RET) encodes a transmembrane receptor tyrosine kinase (RTK). Activation of RET protein which can lead to autophosphorylation of intracellular tyrosine kinase domains, and activating RAS/MAPK, PI3K/AKT, PKC, JAKSTAT and other signaling pathways, leading to tumor cell proliferation, differentiation, distant metastasis, and angiogenesis. RET gene fusion or mutation can drive tumorigenesis, development, and drug resistance. RET mutations are found in 60-90% of medullary thyroid carcinoma (MTC), with the most common mutation site being M918T. RET gene fusion occurs in 10-20% of Papillary Thyroid Carcinoma (PTC) and 2% of Non-Small Cell Lung Cancer (NSCLC), and can also be seen in colorectal cancer, salivary gland cancer, ovarian cancer, and other types of cancer. Preclinical studies showed that TY-1091 has an inhibitory effect on a variety of tumor cells and has good tumor inhibition effects in animal models transplanted subcutaneously with the Ba/ F3-Kif5b-Ret-V804L, Ba/F3-KIF5B-RET LC2/ad (CCDC6-RET) NSCLC, and TT MTC cells (C634W RET, MTC) tumor models with good safety profiles. It is a potent inhibitor that has potential as a treatment for multiple types of tumors carrying active RET alteration, including RET fusion non-small cell lung cancer (NSCLC), RET mutant medullary thyroid cancer (MCT), and other RET alteration solid tumors, and is expected to overcome the bottleneck of resistance to the application of first-generation RET kinase inhibitors.
