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
592 - Effects of novel targeted anticancer drugs on cytotoxicity, apoptosis, angiogenesis, EMT, drug resistance and autophagic mechanism
Presenter: Seyma Aydinlik
Session: Poster Display session 1
Resources:
Abstract
3235 - Delineating the mechanisms of alpha 1-3 fucosyltransferase FUT11 in ovarian cancer
Presenter: Qi Chen
Session: Poster Display session 1
Resources:
Abstract
3577 - The tyrosine kinase inhibitor Dasatinib blocks tumor growth, invasion and recurrence potential by interrupting the communication between cancer cells and their surrounding microenvironment in triple negative breast cancer
Presenter: Miriam Nuncia-Cantarero
Session: Poster Display session 1
Resources:
Abstract
4808 - NORE1A induces a feedback termination of TNF signaling by antagonizing TNFR1 through ITCH-mediated destruction complex
Presenter: Jieun Ahn
Session: Poster Display session 1
Resources:
Abstract
1294 - Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small-cell cell lung cancer cell models
Presenter: Jordi Codony-Servat
Session: Poster Display session 1
Resources:
Abstract
1559 - Expression of IL-17RA promotes cancer stem-like properties of colorectal cancer cells by Stat3 activation
Presenter: Chih-Yung Yang
Session: Poster Display session 1
Resources:
Abstract
1615 - Adaption of Pancreatic Cancer Cells to AKT1 Inhibition Induces the Acquisition of Cancer Stem-Cell Like Phenotype Through Upregulation of Mitochondrial Functions
Presenter: Hugo Arasanz
Session: Poster Display session 1
Resources:
Abstract
4793 - Bub3 is phosphorylated by the Ataxia-Telangiectasia Mutated Kinase in mitosis and required for activation of the mitotic spindle checkpoint in Breast Cancer
Presenter: Mingming Xiao
Session: Poster Display session 1
Resources:
Abstract
1448 - The regulation of INK4 locus by long non-coding RNAs
Presenter: Yojiro Kotake
Session: Poster Display session 1
Resources:
Abstract
1858 - Vascular Endothelial Growth Factor in Colorectal Cancer Pathology, Survival and Treatment
Presenter: Liz Baker
Session: Poster Display session 1
Resources:
Abstract