Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade
RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activa...
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Published in | F1000 research Vol. 5; p. 1005 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London, UK
F1000Research
2016
F1000 Research Ltd |
Subjects | |
Online Access | Get full text |
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Summary: | RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent.
At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments.
In an earlier publication [Newton
et al
, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series. Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile. |
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Bibliography: | new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing interests: There are no competing financial interests to declare. AJW, GH, SH, HB, SH, HNM designed and conducted the biological experiments, AJW, HS and AS conceptualized the experiments, SJ, RN and BW were responsible for chemical design and synthesis and AJ, IW and DO provided strategic direction. AJW prepared the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content. |
ISSN: | 2046-1402 2046-1402 |
DOI: | 10.12688/f1000research.8724.2 |