CH6953755 is an Orally Active and Selective YES1 Kinase Inhibitor
Posted On 2020-01-02
There are reports of YES1 participating in numerous signaling pathways. SRC is a nonreceptor protein tyrosine kinase and is encoded by a proto-oncogene. Besides, the nine members of the SRC family include YES1, SRC, FYN, LYN, and LCK, have various important cellular functions. Moreover, down-regulating YES1 by short hairpin RNA significantly inhibits cell growth in several malignancies, including colon carcinoma, rhabdomyosarcoma, basal-like breast cancer. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of YES1-amplified cancers. Furthermore, YES1 has oncogenic activity displayed the YES1 gene amplification in clinical. It generated an inhibitor that was highly selective against SFK and especially against YES1. Nonetheless, YES1 kinase activity regulated YAP1 activity by nuclear translocation and serine phosphorylation. Specifically, the YAP1 transcriptional activity contributed to the proliferation of the YES1 gene–amplified cancers. CH6953755 is a potent, orally active and selective YES1 kinase inhibitor with anti-cancer activity.
CH6953755 is a potent, orally active and selective YES1 kinase inhibitor with an IC50 of 1.8 nM. Meanwhile, CH6953755 inhibits YES1 kinase leading to antitumor activity against YES1 Gene-amplified cancers in vitro and in vivo. In addition, CH6953755 prevented the autophosphorylation at Tyr426 of YES1 that upregulates enzymatic activity in KYSE70 cells harboring YES1 amplification. YES1 kinase inhibition inhibited the cell growth of YES1-amplified cancer cell lines. After oral treatment of CH6953755 at 60 mg/kg, we observed antitumor activity. Finally, CH6953755 leads to selective antitumor activity against YES1-amplified cancers, both in vitro and in vivo. CH6953755 could be effective in meeting the high unmet medical needs of patients with YES1-amplified cancer. All in all, CH6953755 is a potent, orally active and selective YES1 kinase inhibitor with anti-cancer activity.
Hamanaka N, et al. Cancer Res. 2019 Nov 15;79(22):5734-5745.