ROS1/TRK/ALK inhibitor TY-2136b

An orally bioavailable inhibitor of multiple kinases, including the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and the tropomyosin-related-kinase (tyrosine receptor kinase; TRK), with potential antineoplastic activity. Upon oral administration, ROS1/TRK/ALK inhibitor TY-2136b targets, binds to and inhibits ROS1, TRK, ALK alterations and resistance mutations, including acquired ROS1/TRK/ALK mutations and especially solvent front substitutions such as ROS1 G2032R/TRKA G595R/ALK G1202R mutations as well as other mutations. Inhibition of these kinases leads to the disruption of downstream signaling pathways and the inhibition of cell growth of tumors in which these kinases are overexpressed, rearranged or mutated. TRK, a family of receptor tyrosine kinases (RTKs) activated by neurotrophins, is encoded by neurotrophic tyrosine receptor kinase (NTRK) family genes. The expression of either mutated forms of, or fusion proteins involving, NTRK family members results in uncontrolled TRK signaling, which plays an important role in tumor cell growth, survival, invasion and treatment resistance. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. ROS1, overexpressed and/or mutated in certain cancer cells, plays a key role in cell growth and survival of cancer cells. Compared to other ROS1/TRK/ALK inhibitors, TY-2136b may overcome drug resistance that is caused by acquired solvent-front mutations and may have a better ability to cross the blood-brain-barrier (BBB).