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| Ref Type | Abstract | ||||||||||||
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| Authors | Chengshan Niu; Maolin Zheng; Huan Wang; Kaige Ji; Meihua Li; Guohui Wang; Rongzhen Ni; Apeng Liang; Aishen Gong; Yazhen Zhang; Hui Su; Mingyu Jiang; Shaoqing Chen; Xiugui Chen; Jun Li; Yusheng Wu | ||||||||||||
| Title | Abstract 3419: TY-1091, a highly selective and potent second-generation RET inhibitor, demonstrates superior antitumor activity in multiple RET-mutant models | ||||||||||||
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| URL | https://aacrjournals.org/cancerres/article/83/7_Supplement/3419/720180/Abstract-3419-TY-1091-a-highly-selective-and | ||||||||||||
| Abstract Text | Proto-oncoprotein RET (rearranged during transfection) is a receptor tyrosine kinase and belongs to the cadherin superfamily. RET fusion proteins and gatekeeper mutations represent strong cancer drivers involved in the development of a variety of cancers. Although selective RET inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU667) were recently marketed for patients with RET-dependent NSCLC and thyroid cancers, RET solvent front mutations G810R/S/C/V and other secondary mutations such as Y806C/N and V728A have been identified as mechanisms counting for acquired resistance to the two drugs and limits the applications of the kinase inhibitors. To provide novel RET inhibitors effective to a broader spectrum of RET fusions and mutations, we identified TY-1091 as a novel next-generation RET inhibitor through the in-house RET program and systemic screening of RET compound candidates. TY-1091 was characterized for its anti-tumor activity through in vitro and in vivo testing of a variety of RET-dependent tumor models including a panel of 17 engineered RET mutant Ba/F3 cell lines and 2 cancer cell models. The results show that TY-1091 inhibits wild type and major RET mutants (IC50, nM): RET G810S (9.5 nM), RET V804M/L/E (2.8-12.6 nM), and double mutants RET V804M/G810S (23.5 nM) and M918T/G810S (47.0 nM) through a biochemical screening against a panel of 17 engineered RET mutant Ba/F3 cell lines. Importantly, the inhibitory activity of TY-1091 is much higher than that of first-generation RET inhibitor Cabozantinib, and comparable to other second-generation compounds LOXO-292 and BLU-667. Consistent with its mode of action, TY-1091 grants extraordinary inhibition effects to tumor cell proliferation compared to its peer compounds LOXO-292 and BLU-667 (including TT (thyroid cancer, RET C634W) and LC2/ad (NSCLC, CCDC6-RET)), and the inhibition of the RET pathway activation, i.e., inhibition of RET phosphorylation (IC50 < 1 nM), SHC phosphorylation (IC50 = 4.6 nM) and ERK phosphorylation (IC50 = 9.8 nM) in Ba/F3-KIF5B-RET cells further validated the above in vitro phenotype. The therapeutic potential of TY-1091 was then further validated through mouse pharmacology in that TY-1091 demonstrated remarkable anti-tumor efficacy in a variety of xenograft models including Ba/F3 KIF5B-RET (wt), Ba/F3 KIF5B-RET (V804L), TT (thyroid cancer, RET C634W), and LC2/ad (NSCLC, CCDC6-RET). Detailed data will be presented. In summary, TY-1091 is a highly potent, orally available, and safe small molecule inhibitor to pan-RET mutations in cancer, and may attenuate SFMs-mediated resistance to existing RET therapy. The IND clearance from the US FDA was received and Phase I clinical investigations of TY-1091 shall be launched in the US soon. *To Whom Correspondence should be addressed to: Jun Li, Chengshan Niu and Yusheng Wu | ||||||||||||