The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Rebecca Newton; Katherine Bowler; Emily M Burns; Philip Chapman; Emma Fairweather; Samantha Fritzl; Kristin Goldberg; Niall Hamilton; Sarah Holt; Gemma Hopkins; Stuart Jones; Allan Jordan; Amanda Lyons; Nikki March; Neil Q McDonald; Laura Maguire; Daniel Mould; Andrew G Purkiss; Helen Small; Alexandra Stowell; Graeme Thomson; Ian Waddell; Bohdan Waszkowycz; Amanda Watson; Donald Ogilvie

doi:10.1016/j.ejmech.2016.01.039

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Rebecca Newton, Katherine Bowler, Emily M Burns, Philip Chapman, Emma Fairweather, Samantha Fritzl, Kristin Goldberg, Niall Hamilton, Sarah Holt, Gemma Hopkins, Stuart Jones, Allan Jordan, Amanda Lyons, Nikki March, Neil Q McDonald, Laura Maguire, Daniel Mould, Andrew G Purkiss, Helen Small, Alexandra StowellGraeme Thomson, Ian Waddell, Bohdan Waszkowycz, Amanda Watson, Donald Ogilvie

Research output: Contribution to journal › Article › peer-review

Abstract

Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.

Original language	English
Pages (from-to)	20-32
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	112
DOIs	https://doi.org/10.1016/j.ejmech.2016.01.039
Publication status	Published - 13 Apr 2016

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10.1016/j.ejmech.2016.01.039

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Newton, R., Bowler, K., Burns, E. M., Chapman, P., Fairweather, E., Fritzl, S., Goldberg, K., Hamilton, N., Holt, S., Hopkins, G., Jones, S., Jordan, A., Lyons, A., March, N., McDonald, N. Q., Maguire, L., Mould, D., Purkiss, A. G., Small, H., ... Ogilvie, D. (2016). The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. European Journal of Medicinal Chemistry, 112, 20-32. https://doi.org/10.1016/j.ejmech.2016.01.039

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title = "The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity",

abstract = "Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.",

author = "Rebecca Newton and Katherine Bowler and Burns, {Emily M} and Philip Chapman and Emma Fairweather and Samantha Fritzl and Kristin Goldberg and Niall Hamilton and Sarah Holt and Gemma Hopkins and Stuart Jones and Allan Jordan and Amanda Lyons and Nikki March and McDonald, {Neil Q} and Laura Maguire and Daniel Mould and Purkiss, {Andrew G} and Helen Small and Alexandra Stowell and Graeme Thomson and Ian Waddell and Bohdan Waszkowycz and Amanda Watson and Donald Ogilvie",

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doi = "10.1016/j.ejmech.2016.01.039",

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Newton, R, Bowler, K, Burns, EM, Chapman, P, Fairweather, E, Fritzl, S, Goldberg, K, Hamilton, N, Holt, S, Hopkins, G, Jones, S, Jordan, A, Lyons, A, March, N, McDonald, NQ, Maguire, L, Mould, D, Purkiss, AG, Small, H, Stowell, A, Thomson, G, Waddell, I, Waszkowycz, B, Watson, A & Ogilvie, D 2016, 'The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity', European Journal of Medicinal Chemistry, vol. 112, pp. 20-32. https://doi.org/10.1016/j.ejmech.2016.01.039

TY - JOUR

T1 - The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

AU - Newton, Rebecca

AU - Bowler, Katherine

AU - Burns, Emily M

AU - Chapman, Philip

AU - Fairweather, Emma

AU - Fritzl, Samantha

AU - Goldberg, Kristin

AU - Hamilton, Niall

AU - Holt, Sarah

AU - Hopkins, Gemma

AU - Jones, Stuart

AU - Jordan, Allan

AU - Lyons, Amanda

AU - March, Nikki

AU - McDonald, Neil Q

AU - Maguire, Laura

AU - Mould, Daniel

AU - Purkiss, Andrew G

AU - Small, Helen

AU - Stowell, Alexandra

AU - Thomson, Graeme

AU - Waddell, Ian

AU - Waszkowycz, Bohdan

AU - Watson, Amanda

AU - Ogilvie, Donald

PY - 2016/4/13

Y1 - 2016/4/13

N2 - Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.

AB - Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.

U2 - 10.1016/j.ejmech.2016.01.039

DO - 10.1016/j.ejmech.2016.01.039

M3 - Article

C2 - 26874741

SN - 0223-5234

VL - 112

SP - 20

EP - 32

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

Abstract

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