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 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.
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Amanda J
AJ
Watson
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Gemma V
GV
Hopkins
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Samantha
S
Hitchin
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Habiba
H
Begum
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Stuart
S
Jones
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Allan
A
Jordan
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Sarah
S
Holt
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
H Nikki
HN
March
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Rebecca
R
Newton
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Helen
H
Small
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Alex
A
Stowell
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Ian D
ID
Waddell
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Bohdan
B
Waszkowycz
Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Donald J
DJ
Ogilvie
KDR; Lung adenocarcinoma; RET; Screening cascade; Selectivity