TRK/ROS1/ALK inhibitor SIM1803-1A

An orally available 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, TRK/ROS1/ALK inhibitor SIM1803-1A targets, binds to and inhibits wild-type, point mutants and fusion proteins of ALK, ROS1, and TRK, including fusion proteins containing sequences from neurotrophic tyrosine receptor kinase (NTRK) types 1 (NTRK1; TrkA), 2 (NTRK2; TrkB), and 3 (NTRK3; TrkC). 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 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 in certain cancer cells, plays a key role in cell growth and survival of cancer cells.