Abstract P06-02: Discovery of TAS0953/HM06, a novel next generation RET-specific inhibitor capable of inhibiting RET solvent front mutations
Authors: Miyazaki Isao , Ishida Keiji , Kato Masanori , Suzuki Tatsuya , Fujita Hidenori , Ohkubo Shuichi , Iwasawa Yoshikazu 
Published: December 2021

Abstract
RET gene fusions are oncogenic drivers in multiple tumor types and are estimated to be present in 1% to 2% of non-squamous non-small cell lung cancers (NSCLCs). Although the first-generation selective RET inhibitors selpercatinib and pralsetinib show clinical antitumor activity in NSCLCs, acquired resistances driven by RET solvent front mutation (G810R/S/C) have emerged. In such cases, no other treatment options are currently available for these patients after relapse with selpercatinib or pralsetinib. TAS0953/HM06, a novel adenosine triphosphate-competitive and highly selective RET inhibitor, is a next-generation RET inhibitor that may overcome solvent front mutant resistance. We performed a panel test of 254 kinases and found that 23-nM TAS0953/HM06 displayed only RET inhibition as plotted over 50% inhibited kinases. TAS0953/HM06 potently inhibits recombinant wild-type (WT) RET at sub-nanomolar concentrations that are similar to the IC50 values of selpercatinib and pralsetinib in WT RET. We investigated the cellular potencies against RET WT fusions and RET mutations, including the gatekeeper mutations V804L/M and selpercatinib- or pralsetinib-resistant mutations G810R/S, in engineered BA/F3 cells. TAS0953/HM06 inhibited the growth of the RET fusion overexpressed in Ba/F3 cells, including both the V804M/L and G810R/S RET mutations and WT RET. In addition, we examined the crystal structure of the RET kinase domain complexed with an analogue of TAS0953/HM06. X-ray crystal structures of the complex revealed that the analogue has unique binding mode to RET respect to selpercatinib and pralsetinib: it does not fill the space in the direction of the side chain of G810, suggesting that TAS0953/HM06 effectively circumvents steric hindrance from solvent front substitutions. This feature likely contributes to the ability of TAS0953/HM06 to maintain its biological potency in G810 mutations. Finally, we evaluated the antitumor activity of various doses of TAS0953/HM06 in xenograft tumor model derived from Ba/F3 cells from mice expressing WT or G810R KIF5B-RET (these mice show resistance to selpercatinib and pralsetinib). A Doses as low as of 10 mg/kg twice a day, TAS0953/HM06 were able to significantly inhibit tumor growth and phospho-RET. Taken together, the results show that, in addition to its selective high potency against WT RET, TAS0953/HM06 shows significant potency against G810R solvent front mutation which is highly resistant to selpercatinib and pralsetinib, in vitro and in vivo. Therefore, TAS0953/HM06 might represent a new therapeutic option for patients with RET mutations, including those resistant to 1st generation selective RET inhibitors. The safety and efficacy of TAS0953/HM06 are currently being investigated in a phase 1/2 clinical trials (NCT04683250).
Citation Format: Isao Miyazaki, Keiji Ishida, Masanori Kato, Tatsuya Suzuki, Hidenori Fujita, Shuichi Ohkubo, Yoshikazu Iwasawa. Discovery of TAS0953/HM06, a novel next generation RET-specific inhibitor capable of inhibiting RET solvent front mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P06-02.