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
1735 - mTOR inhibition in the treatment of resistant breast cancer
Presenter: María Rodriguez
Session: Poster Display session 1
Resources:
Abstract
6068 - Study of Photodynamic therapy in vitro
Presenter: Irene Jiménez Munguía
Session: Poster Display session 1
Resources:
Abstract
3011 - The potential of neratinib plus dasatinib in overcoming and preventing neratinib resistance in HER2-positive breast cancer models
Presenter: Neil Conlon
Session: Poster Display session 1
Resources:
Abstract
2644 - Novel HDACi, MHY446, induces apoptosis via regulation of mitochondria-endoplasmic reticulum interaction in HCT116 human colorectal cancer cells
Presenter: Nam Deuk Kim
Session: Poster Display session 1
Resources:
Abstract
3085 - Dual inhibition of TGF-β and AXL as a novel treatment for colorectal cancer
Presenter: Davide Ciardiello
Session: Poster Display session 1
Resources:
Abstract
1314 - PARP inhibition enhances cisplatin sensitivity in cervical cancer by modulating β-catenin signaling
Presenter: Minakshi Mann
Session: Poster Display session 1
Resources:
Abstract
2417 - Synergistic effect of DSF combined treatment with cisplatin in atypical teratoid/rhabdoid tumors (AT/RT)
Presenter: Seung Ah Choi
Session: Poster Display session 1
Resources:
Abstract
1149 - Reactive oxygen species induced by OSU-A9 inhibit the growth of duodenal cancer and gastric cancer cells through dephosphorylating intranuclear pyruvate kinase muscle isozyme M2
Presenter: Li-Yuan Bai
Session: Poster Display session 1
Resources:
Abstract
1862 - New therapy for intrahepatic cholangiocarcinoma targeted to cancer associated fibroblasts
Presenter: Takahiro Yamanaka
Session: Poster Display session 1
Resources:
Abstract
782 - Macrophage-cancer cell fusion is mediated by Phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation
Presenter: Ivan Shabo
Session: Poster Display session 1
Resources:
Abstract