Targeting the M-Ras and B/C-Raf kinases by allosteric druglike inhibitors for cancer therapy

Abstract

Presented here is a computational design of druglike allosteric inhibitors of the M-Ras, B-Raf, and C-Raf kinases. The Ras and Raf kinases are important for cell proliferation. Their mutations can lead to cancer formation. MAPK pathways, important in the cell cycle, are stimulated when Ras activates Raf. Numerous drugs are MAPK inhibitors. Yet, bypass signaling is often established, causing drug resistance. B-Raf inhibitors efficiently inhibit certain MAPK kinases. Nevertheless, they can also activate C-Raf in Ras-mutated cancers, so their signaling is switched from B-Raf to C-Raf. M-Ras can bypass other mutated Ras kinases, leading to cancer advancement. Thus, M-Ras and B/C-Raf are desirable drug targets. Most inhibitors attach to the kinases’ catalytic sites. Since these sites are similar in kinases, they are hard to target selectively. Allosteric sites differ in kinases, which allows selective binding. The M-Ras, B-Raf, and C-Raf allosteric binding sites were studied in the Deep View program. New small-molecule inhibitors were designed by systematic atomic substitutions in known inhibitors. The Data Warrior and Molinspiration programs calculated druglike properties of the designed molecules. The molecules with the best druglike properties and no toxicities were docked in ArgusLab. Their binding energies were found. One of the designed molecules bonded well allosterically to B-Raf, C-Raf, and M-Ras and had better druglike properties than the known single-kinase inhibitors. These findings, combined with earlier experimental studies, indicate the molecule designed here may be an effective allosteric inhibitor of all three kinases, and may offer enhanced therapies for cancers with Raf or Ras mutations.