"RB-reactivator screening" as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist)

by Selleckchem | May 27 2023

The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.

Comments：

It is fascinating to learn about the work on the RB-reactivator screening and how it led to the discovery of novel molecular-targeting agents. The hypothesis that most molecular-targeting agents against activated oncogenes may reactivate the function of RB is a significant contribution to cancer research. The screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, to convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form is a brilliant idea.

It is remarkable that using this screening system, the discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. The discovery of trametinib and its approval as the first-in-class MEK inhibitor is a significant milestone in cancer treatment, and it's inspiring to learn that it was selected as the Drug Discovery of the Year by the British Pharmacological Society.

Moreover, the approval of the combination of trametinib and the BRAF inhibitor dabrafenib for advanced BRAF mutant melanoma, non-small cell lung cancer, and anaplastic thyroid cancer in the USA, EU, Japan, and many other countries is a testament to the importance of the work. The fact that the US FDA granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015 shows the potential of the discovery to impact cancer treatment positively.

Overall, the work is an excellent example of how basic research can lead to the discovery of novel molecular-targeting agents that can have a significant impact on cancer treatment.