Explore the discovery journey of non-small cell lung cancer drugs from Crizotinib, Ceritinib, etc.

Preface

Non-small cell lung cancer is one of the most common malignant tumors in the world, and it poses a great threat to human health.

Crizotinib's research and development journey

In order to develop a new type of c-Met inhibitor, Sugen Company of the United States conducted high-throughput screening of thousands of indol-2-one derivatives and found that derivative A has good inhibitory activity against c-Met.

The development of Crizotinib originated from the c-Met inhibitor R&D project of Sugen.

Ceritinib's research and development journey

Novartis used high-throughput screening technology to screen the kinase compound library and found that compound B has a good development prospect.

The liver microsomal metabolism test proved that the derivative B can be oxidized and metabolized into a highly active ionic compound B1, and glutathione can capture the ionic compound and perform an addition reaction to obtain the derivative B2.

Alectinib's research and development journey

Alectinib was developed by Chugai, a Japanese pharmaceutical company controlled by Roche.

Discovery of Brigatinib

ARIAD Pharmaceuticals has a keen interest in the dimethylphosphorus oxide fragment in the SRC inhibitor AP23464.

With the rapid development of molecular biology and high-throughput screening technologies, drug research and development has gradually moved towards "individualization" and "precision".

Reference

[1] A Selectivesmall molecule inhibitor of c -Met kinase inhibits c -Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo.

[2] Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17 -tetrahydro -2H -8,4 -(metheno)pyrazolo [ 4,3 -h] [2,5,11]-benzoxadiaz-acyclotetradecine-3-carbonitrile(PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros on.

[3] Discovery of entrectinib: a new 3 -aminoindazole as a potent anaplastic lymphoma kinase(ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (Pan-TRKs) inhibitor.

[4] Chaptertwenty-five case history: XalkoriTM (Crizotinib), a potent and selective dual inhibitor of mesenchymal epithelial transition (MET) and anaplastic lymphoma kinase (ALK) for cancer treatment.