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
2459 - Does bevacizumab increase joint pain ? Preliminary results of BEVARTHRALGIA Study
Presenter: Vauleon Enora
Session: Poster Display session 1
Resources:
Abstract
4913 - Prostatic cancer androgen deprivation therapy and bone health in carcinoma prostate.
Presenter: Gouri Shankar Bhattacharyya
Session: Poster Display session 1
Resources:
Abstract
1352 - Patterns of care for patients with metastatic bone disease in solid tumors – a cross-sectional study (SAKK 95/16)
Presenter: Michael Mark
Session: Poster Display session 1
Resources:
Abstract
6002 - Infection-Related Mortality in Different Types of Cancers
Presenter: Mohamed Gouda
Session: Poster Display session 1
Resources:
Abstract
5643 - Survival Trends in Critically ill Oncology Patients: impact of patient’s eligibility to post-ICU chemotherapy
Presenter: Edith Borcoman
Session: Poster Display session 1
Resources:
Abstract
3097 - Development and validation of a multivariable prediction model for 6-month mortality in older cancer patients: the GeriAtrIc-Tumor Score of PrEdiction for Early Death (GAIT SPEED)
Presenter: Angeli Angeli
Session: Poster Display session 1
Resources:
Abstract
856 - A Longitudinal Tracking and Quantitative Assessment of Paclitaxel-Induced Peripheral Neurotoxicity
Presenter: Ayumu Matsuoka
Session: Poster Display session 1
Resources:
Abstract
1662 - Efficiency of controlled cryotherapy in prevention of chemotherapy induced peripheral neuropathy (CIPN)
Presenter: Trudi Schaper
Session: Poster Display session 1
Resources:
Abstract
2766 - The Validity of Evaluations for Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Presenter: Teppei Yamada
Session: Poster Display session 1
Resources:
Abstract
5683 - Prevention of chemoradiation-related mucositis in patients with head and neck cancer using dexamethasone-based mouthwash: A phase II randomized double-blind, placebo-controlled study
Presenter: Naiyarat Prasongsook
Session: Poster Display session 1
Resources:
Abstract