Definition

An orally bioavailable small molecule inhibitor of multiple kinases, including tropomyosin-related-kinase (TRK) and rearranged during transfection (RET), with potential antineoplastic activity. Upon oral administration, TRK/RET inhibitor ND-003 targets and binds to TRK and fusion proteins containing sequences from neurotrophic tyrosine receptor kinase (NTRK). This inhibits neurotrophin-TRK interaction and TRK activation, thereby preventing the activation of downstream signaling pathways, including the PI3K, RAS/MAPK/ERK and PLC-gamma pathways that are activated by these kinases. This results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress TRK and/or express NTRK fusion proteins. TRK/RET inhibitor ND-003 also targets and binds to RET, thereby inhibiting the activity of RET. This results in an inhibition of cell growth of tumors that exhibit increased RET activity. 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. RET overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types. Dysregulated RET activity plays a key role in the development and progression of certain cancers.