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Ref Type abstract
Authors Gabrielle R. Kolakowski, Erin D. Anderson, Joshua A. Ballard, Barbara J. Brandhuber, Kevin R. Condroski, Eliana B. Gomez, Thomas C. Irvin, Manoj Kumar, Nisha A. Patel, Faith D. Watson and Steven W. Andrews
Title Abstract 1464: Pre-clinical characterization of potent and selective next-generation RET inhibitors
Abstract Text In May 2020, selpercatinib became the first FDA-approved selective RET inhibitor, indicated for patients (pts) with RET fusion-positive NSCLC and thyroid cancer as well as RET-mutant medullary thyroid cancer. Despite the durable activity of selpercatinib, pts can eventually develop acquired resistance. Previous studies in pts treated with selpercatinib or pralsetinib have reported the shared emergence of recurrent RET G810 mutations at the solvent front of the ATP pocket, which lead to a steric clash and loss of binding potency for both drugs. In some pts, these RET G810 solvent front mutations have been observed to co-occur with RET V804 gatekeeper mutations, demonstrating the importance of identifying agents that can maintain potency against both solvent front and gatekeeper resistance mutations. While multi-kinase inhibitors with potency against RET G810 mutations have been reported, these agents lack activity against V804 mutations and also carry off-target toxicities that further limit efficacy. We have identified a series of potent and selective next-generation RET inhibitors to address the emerging unmet need of pts who relapse on selective RET inhibitors. To assess potency, we evaluated the molecules in HEK293 cell lines engineered to express an M918T RET mutation or a KIF5B-RET fusion, as well as G810S or V804M resistance mutations. One compound, LOX-18228, exhibited nanomolar potency across the M918T RET, KIF5B-RET wild type, KIF5B-RET G810S, KIF5B-RET V804M, and KIF5B-RET V804M/G810S cell lines, with cellular IC50 values of 1.2, 0.9, 5.8, 31 and 51 nM, respectively. LOX-18228 also demonstrated high selectivity for RET when compared to a broad enzyme panel of off-target kinases, followed by relevant cellular assay screening. LOX-18228 also showed robust selectivity against a diverse panel of receptors, transporters and enzymes at a concentration of 10 μM, and exhibited a hERG IC50 of >30 μM. LOX-18228 demonstrated in vitro ADME properties predictive of good in vivo exposure with low predicted intrinsic clearance (range, 2.1-6.6 µL/min/million cells) in human, mouse, rat, and dog hepatocytes, and a measured high bin permeability of Papp = 15 (10-6 cm/s) in an intestinal MDCKII permeability assay. As predicted, LOX-18228 demonstrated high oral exposures in mouse and rat. In a pt-derived xenograft (PDX) model harboring a CCDC6-RET G810S mutation, LOX-18228 demonstrated complete regression at doses ≥30 mg/kg. Similarly, in a PDX model harboring a CCDC6-RET V804M mutation, LOX-18228 exhibited dose-dependent tumor inhibition with 100% tumor growth inhibition observed at 60 mg/kg. These data suggest that LOX-18228, as well as closely related compounds, represent promising next-generation RET inhibitor candidates that could be used to further extend durable disease control for pts with RET-altered cancers following the development of acquired resistance to current agents. An IND is planned for 2021.


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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
LOX-18228 LOX-18228 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
LOX-18228 LOX 18228|LOX18228 RET Inhibitor 52 LOX-18228 is a next-generation RET inhibitor, potentially resulting in decreased cell growth, inhibition of tumor growth, and tumor regression (Cancer Res 2021;81(13_Suppl):Abstract nr 1464).
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 M918T Advanced Solid Tumor predicted - sensitive LOX-18228 Preclinical - Cell culture Actionable In a preclinical study, LOX-18228 treatment resulted in reduced viability in a cell line expressing RET M918T in culture (Cancer Res 2021;81(13_Suppl):Abstract nr 1464). detail...