The transmembrane proto-oncogene receptor tyrosine kinase (RTK) ROS is one of the last two remaining orphan receptor tyrosine kinases. The ectopic expression, as well as the production of variable mutant forms of ROS kinase, has been reported in a number of cancers, such as glioblastoma multiforme, and non-small cell lung cancer, suggesting a role for ROS kinase in deriving such tumors. ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma, non-small-cell lung cancer (NSCLC), and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors.

Taletrectinib (also known as DS-6051b, AB-106 or IBI-344) is a potent, orally active, and next-generation selective ROS1/NTRK inhibitor.

Taletrectinib potently inhibits recombinant ROS1, NTRK1, NTRK2, and NTRK3 in sub-nanomolar concentration in an ATP-competitive manner. In addition, Taletrectinib also inhibits ROS1 G2032R and other Crizotinib-resistant ROS1 mutants. Taletrectinib inhibits the growth of the CD74-ROS1 overexpressed Ba/F3 cells and the ROS1 fusion-positive HCC78 cancer cell line. Moreover, Taletrectinib potently inhibits autophosphorylation of ROS1 in CD74-ROS1-expressed Ba/F3 cells and the SLC34A2-ROS1 harboring HCC78 cells. Furthermore, in lung cancer PDX model harboring CD74-ROS1 fusion gene, Taletrectinib markedly inhibits tumor growth without significant body weight loss. Besides, in CD74-ROS1 mutants expressing Ba/F3-bearing mice, Taletrectinib inhibits tumor growth and phospho-ROS1 in a dose-dependent manner. As expected, Taletrectinib almost completely inhibits phospho-ROS1 of wild-type- and G2032R-mutated CD74-ROS1 in vivo.

Beyond that, Taletrectinib can also inhibit ALK in vitro kinase assay, and inhibits growth of EML4-ALK expressing Ba/F3 cells. Taletrectinib exerts moderate inhibitory activity on the growth of ALK rearranged patients’ derived cell line models harboring various resistance mechanisms.

In summary, Taletrectinib is an orally active and selective ROS1/NTRK inhibitor that can be used for the study of ROS1-rearranged cancer, and NTRKs-rearranged cancers.

[1] Ryohei Katayama, et al. Nat Commun. 2019 Aug 9;10(1):3604.