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Ref Type Abstract
PMID
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
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

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
TY-1091 TY-1091 7 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
TY-1091 TY 1091|TY1091 RET Inhibitor 52 TY-1091 inhibits RET, potentially resulting in decreased tumor growth (Cancer Res (2023) 83 (7_Supplement): 3419).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET G810S Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Cell culture Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET G810S in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...
RET V804L Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Biochemical Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET V804L in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...
RET V804M Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Biochemical Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET V804M in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...
RET V804M RET G810S Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Biochemical Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET G810S and V804M in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...
RET G810S RET M918T Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Biochemical Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET G810S and M918T in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...
RET V804E Advanced Solid Tumor predicted - sensitive TY-1091 Preclinical - Biochemical Actionable In a preclinical study, TY-1091 inhibited activity in a cell line expressing RET V804E in culture (Cancer Res (2023) 83 (7_Supplement): 3419). detail...
RET C634W thyroid cancer predicted - sensitive TY-1091 Preclinical - Cell line xenograft Actionable In a preclinical study, TY-1091 inhibited proliferation in a thyroid cancer cell line harboring RET C634W in culture and inhibited tumor growth in a cell line xenograft model (Cancer Res (2023) 83 (7_Supplement): 3419). detail...