Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations

被引：2

作者：

Mccoull, William ^{[1
]}

Thomson, Clare ^{[1
]}

Braybrooke, Erin ^{[1
]}

Chan, Christina ^{[1
]}

Colclough, Nicola ^{[1
]}

Gonzalez, Miguel A. Cortes ^{[2
,3
]}

Cosulich, Sabina ^{[1
]}

Davies, Nichola L. ^{[1
]}

Floc'h, Nicolas ^{[1
]}

Greenwood, Ryan ^{[1
]}

Hargreaves, David ^{[1
]}

Huang, Peng ^{[4
]}

Hunt, Thomas A. ^{[1
]}

Johnson, Tony ^{[1
]}

Johnstrom, Peter ^{[2
,3
,7
]}

Kettle, Jason G. ^{[1
]}

Kondrashov, Mikhail ^{[2
,3
]}

Kostomiris, Demetrios H. ^{[5
,6
]}

Li, Songlei ^{[4
]}

Lister, Andrew ^{[1
]}

Martin, Scott ^{[1
]}

Mckerrecher, Darren ^{[1
]}

Mclean, Neville ^{[1
]}

Nissink, J. Willem M. ^{[1
]}

Orme, Jonathan P. ^{[1
]}

Orwig, Paige ^{[1
]}

Packer, Martin J. ^{[1
]}

Pearson, Stuart ^{[1
]}

Qin, Lina ^{[4
]}

Felisberto-Rodrigues, Catarina ^{[1
]}

Savoca, Adriana ^{[1
]}

Schou, Magnus ^{[2
,3
,7
]}

Stokes, Stephen ^{[1
]}

Swaih, Aisha M. ^{[1
]}

Talbot, Sara ^{[1
]}

Tucker, Michael J. ^{[1
]}

Ward, Richard A. ^{[1
]}

Wadforth, Emma ^{[1
]}

Wang, Chunli ^{[4
]}

Wilson, Joanne ^{[4
]}

Yang, Yawen ^{[4
]}

机构：

[1] AstraZeneca, Cambridge CB2 0AA, England

[2] Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, SE-17176 Stockholm, Sweden

[3] Stockholm Cty Council, SE-17176 Stockholm, Sweden

[4] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

[5] AstraZeneca, BioPharmaceut R&D, Discovery Sci, Waltham, MA 02451 USA

[6] Francis Crick Inst, MSD London Discovery Ctr, 1 Midland Rd, London NW1 1AT, England

[7] AstraZeneca, PET Sci Ctr, Precis Med & Biosamples, Oncol R&D, SE-17176 Stockholm, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 03期

关键词：

GROWTH-FACTOR RECEPTOR; RESISTANCE; CANCER;

D O I：

10.1021/acs.jmedchem.4c02811

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether 23 and biaryl 36 as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne 5 which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CLint compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.

引用

页码：3700 / 3748

页数：49

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