The preclinical development of regorafenib for the treatment of colorectal cancer.

INTRODUCTION: The RAS-RAF-MEK-ERK pathway is one of the best characterized kinase cascades. During the exploration of small molecules that inhibit RAF1 kinase, regorafenib (BAY 73-4506) was discovered as a multikinase inhibitor which demonstrated anti-cancer, anti-angiogenic, and apoptotic activities in metastatic colorectal cancer. This was not the first multikinase inhibitor discovered for the disease; indeed, before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012, sorafenib (BAY 43-9006) had already been developed to be the first in the world as a multikinase inhibitor for malignancy. Indeed, the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile, both as a kinase inhibitor as well as in its clinical application. AREAS COVERED: In this drug discovery case history, the authors review the design, discovery, and development of both regorafenib and sorafenib from back in the 1990s. Furthermore, the authors highlight the drug's anti-cancer and anti-angiogenic properties as well as its efficacy, safety pharmacology and toxicology based on FDA documents. EXPERT OPINION: In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently, our understanding of drug discovery, the approaches for kinase profiling, and technologies needed for their development are paramount. Indeed, the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics. Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive.