Abstract 4307
Background
Oncogenic activation of the receptor tyrosine kinase (RTK) RET via point mutation or genomic rearrangement has been identified in multiple cancers, including medullary and papillary thyroid cancers, and non-small cell lung cancer (NSCLC). Two multi-kinase RET inhibitors vandetanib and cabozantinib have been approved for thyroid cancer. Current investigational RET inhibitors BLU-667 and LOXO-292 have demonstrated efficacy in RET aberrant NSCLC and thyroid cancers. Multiple resistance mutations have been reported from preclinical studies, including the gatekeeper mutation V804L to cabozantinib and solvent front mutations (SFMs) G810A/S to vandetanib. Given that current TKIs often lead to resistance, TPX-0046, a next generation RET inhibitor that is structurally differentiated and potent against various mutations, especially SFMs, was designed.
Methods
A series of macrocyclic RET inhibitors were rationally designed and characterized in RET-related biological assays. TPX-0046 was further evaluated in RET-driven tumor models in vivo.
Results
TPX-0046 is a potent and selective next-generation RET/SRC inhibitor with a small and rigid macrocyclic structure that is structurally differentiated from current RET inhibitors. In enzymatic assays, TPX-0046 demonstrated low nanomolar potency against WT and many mutated RETs, as well as SRC, and is VEGFR2-sparing. TPX-0046 potently inhibited RET phosphorylation and cell proliferation in in-house engineered Ba/F3 KIF5B-RET, TT, and LC2/ad cells with IC50s of approximately 1 nM. TPX-0046 is potent against the SFM G810R in Ba/F3 cell proliferation assay with a mean IC50 of 17 nM, whereas comparable proxy molecules for BLU-667 and LOXO-292 have IC50s >500 nM. TPX-0046 demonstrated marked anti-tumor efficacy in vivo in multiple RET-driven cancer cell-derived and patient-derived xenograft tumor models.
Conclusions
TPX-0046 is a novel next generation RET/SRC inhibitor with favorable pharmaceutical properties and possesses potent in vitro and in vivo activity against diverse RET alterations, including the SFM G810R. The novel macrocyclic structure may provide opportunities to overcome treatment resistance from current RET inhibitors. TPX-0046 is currently in IND-enabling studies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Turning Point Therapeutics, Inc.
Funding
Turning Point Therapeutics, Inc.
Disclosure
E. Rogers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. D. Zhai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. W. Deng: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. X. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. D. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. J. Ung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. J. Whitten: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. H. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. J. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. T. Hu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. H. Zhuang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. Y. Lu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. Z. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. A. Graber: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. Z. Zimmerman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. R. Xin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics, Inc. J..J. Cui: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Turning Point Therapeutics. All other authors have declared no conflicts of interest.
Resources from the same session
4925 - Prognostic role of CD73 in metastatic Non Small Cell Lung Cancer according to the presence of driver alterations
Presenter: Giulia Galli
Session: Poster Display session 1
Resources:
Abstract
785 - JAK-STAT inhibitor overcomes interferon γ-reduced, NK cell-mediated cytotoxicity in non-small-cell lung cancer cells
Presenter: Riki Okita
Session: Poster Display session 1
Resources:
Abstract
2326 - Low LATS2 expression is associated with poor prognosis in non small cell lung cancer
Presenter: Si-hyong Jang
Session: Poster Display session 1
Resources:
Abstract
5960 - Application of ESCAT and OncoKB scales in Liquid biopsy (LB) in Advanced NSCLC patients (pts): Is it feasible and reliable?
Presenter: Michael McCusker
Session: Poster Display session 1
Resources:
Abstract
4855 - IDH1R132H mutation induces a less aggressive phenotype of glioma cells and affects the radiosensitivity by interacting with Wnt/β-catenin signaling
Presenter: Xuetao Han
Session: Poster Display session 1
Resources:
Abstract
2641 - Impact of Angiopoietin-2 on glioblastoma response to combined chemo-radiotherapy
Presenter: Charly Helaine
Session: Poster Display session 1
Resources:
Abstract
5743 - The Discovery of RNA-aptamers That Selectively Bind and Inhibit Glioblastoma Stem Cells by targeting EphA2
Presenter: Alessandra Affinito
Session: Poster Display session 1
Resources:
Abstract
4160 - Impact of tumor reoxygenation by nanoparticles on Tumor Associated Macrophages (TAMs)
Presenter: Aurélie Ferré
Session: Poster Display session 1
Resources:
Abstract
2474 - Prognostic significance of c-Rel/p50 heterodimer in the tumor microenvironment of uveal melanoma
Presenter: Seema Kashyap
Session: Poster Display session 1
Resources:
Abstract
1769 - Synergistic role of BAP1 and DNA damage response pathway in uveal melanoma and its prognostic significance.
Presenter: JAYANTI JHA
Session: Poster Display session 1
Resources:
Abstract