Definition

An orally available dual inhibitor of the receptor tyrosine kinase c-ros oncogene 1 (ROS1) and the tropomyosin-related-kinase (tyrosine receptor kinase; TRK), with potential antineoplastic activity. Upon oral administration, pan-TRK/ROS1 dual inhibitor XZP-5955 targets, binds to and inhibits wild-type, point mutants and fusion proteins of 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). It specifically inhibits proliferation of tumor cells harboring certain TRK and ROS1 resistance mutations, such as TRKA G595R, TRKC G623R, TRKA G667C and ROS1 G2032R. 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. ROS1, overexpressed in certain cancer cells, plays a key role in cell growth and survival of cancer cells. XZP-5955 is able to penetrate the blood-brain barrier (BBB).