Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade.
AuthorsWatson, Amanda J
Hopkins, Gemma V
Jordan, Allan M
Holt, Sarah V
March, H Nikki
Small, Helen F
Stowell, Alexandra I J
Waddell, Ian D
Ogilvie, Donald J
AffiliationCancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester
MetadataShow full item record
AbstractRET (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.
CitationIdentification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade. 2016, 5:1005 F1000Res
- The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
- Authors: Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJR, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AIJ, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ
- Issue date: 2016 Apr 13
- High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma.
- Authors: Dunna NR, Kandula V, Girdhar A, Pudutha A, Hussain T, Bandaru S, Nayarisseri A
- Issue date: 2015
- In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer.
- Authors: Bentzien F, Zuzow M, Heald N, Gibson A, Shi Y, Goon L, Yu P, Engst S, Zhang W, Huang D, Zhao L, Vysotskaia V, Chu F, Bautista R, Cancilla B, Lamb P, Joly AH, Yakes FM
- Issue date: 2013 Dec
- State-of-the-Art Strategies for Targeting <i>RET</i>-Dependent Cancers.
- Authors: Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F
- Issue date: 2020 Apr 10
- Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers.
- Authors: Roskoski R Jr, Sadeghi-Nejad A
- Issue date: 2018 Feb