Discovery of highly potent V600E-B-RAF kinase inhibitors: Molecular Modeling Study

There is an increasing interest in the search for potent kinase inhibitors for the treatment of cancer. This is based on the knowledge that oncogenic mutation activates the overexpression of wild-type B-RAF kinase signaling pathways, which plays a major role in the proliferation and progression of different types of cancer cells.

Previous research studies have indicated that V600E-B-RAF is a suitable drug target for the treatment of colorectal cancer, melanoma, thyroid carcinoma, Non-Hodgkin lymphoma, hairy cell leukemia, and non-small cell lung carcinoma. Notable examples of V600E-B-RAF kinase inhibitory drugs include Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib. Triarylpyrazole derivatives that contain either urea or amide linker can be used as anti-proliferative agents for the treatment of cancer.

Professor Chang-Hyun Oh from University of Science and Technology in South Korea and his research team developed a series of twenty triarylpyrazole derivatives and demonstrated their potency and structure-activity relationship against V600E-B-RAF kinase. The authors carried out molecular modeling studies to garner deeper insights about the binding characteristics and structural features of triarylpyrazole derivatives (containing urea or amide linker) that would foster their future development as potent V600E-BRAF kinase inhibitors.

The research team found that the target compounds that contain a hydroxyl group on the aryl ring attached to the third position of the pyrazole ring were more potent compared to corresponding methoxy analogues of the compound, while the target compounds that contain urea linkers exhibited superior potency compared to corresponding diarylamide analogues of the compound. They also observed that 4ꞌ-chloro-3ꞌ-(trifluoromethyl)-phenyl was the most potent compound among the diarylurea derivatives, while 4ꞌ-morpholino-3ꞌ-(trifluoromethyl)-phenyl was the most potent compound among the diarylamides derivatives.

In addition, the authors found that all the target compounds shared a conserved and common binding mode within the mutant B-RAF kinase site. The target compounds exhibited a type-IIA inhibition pattern via interactions with specific amino acid residues (i.e. Glu-501, Cys-532, Gln530, Asp-594, and Phe-595) within the V600E-B-RAF kinase active site. It was also discovered that variables such as molecular geometry, shape, ionization, and how well the target compounds satisfy Lipinski’s rule of 5 directly influenced the bioactivity of triarylpyrazole derivatives containing urea or amide linker. Furthermore, the presence of multiple HBA/HBD (O-probe/ N1-probe) sites and steric constraints were identified as important pharmacophoric features that correlate positively with the improved bioactivity of triarylpyrazole derivatives containing urea or amide linker.

In a nutshell, Professor Chang-Hyun Oh and colleagues successfully discovered that the presence of a urea linker or hydroxyl group contributes to the maximum activity of target compounds. The novel findings explicated in their study provides compelling evidence that specific bioactivity variables and pharmacophoric features directly influence the potency of triarylpyrazole derivatives containing urea or amide linker. The study will serve as a basis for the future development and use of this series of target compounds for the anti-proliferative treatment of cancer and other disorders.