NMR in integrated biophysical drug discovery for RAS: past, present, and future
| Autor: | Teklab Gebregiworgis, Christopher B. Marshall, Fenneke KleinJan, Geneviève M.C. Gasmi-Seabrook, Ben J Eves, Masahiro Enomoto, Ningdi F Liu, Ki-Young Lee, Mitsuhiko Ikura, Zhenhao Fang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
GTP' Druggability GTPase 010402 general chemistry 01 natural sciences Biochemistry Proto-Oncogene Proteins p21(ras) Small Molecule Libraries 03 medical and health sciences Prenylation Drug Discovery Guanine Nucleotide Exchange Factors Humans Nuclear Magnetic Resonance Biomolecular Spectroscopy Ras Inhibitor Cyclic Nucleotide Phosphodiesterases Type 6 Chemistry Drug discovery Effector Membrane Proteins 0104 chemical sciences 3. Good health Cell biology 030104 developmental biology Mutation Lipid modification Protein Binding Signal Transduction |
| Zdroj: | Journal of Biomolecular NMR. 74:531-554 |
| ISSN: | 1573-5001 0925-2738 |
| DOI: | 10.1007/s10858-020-00338-6 |
| Popis: | Mutations in RAS oncogenes occur in ~ 30% of human cancers, with KRAS being the most frequently altered isoform. RAS proteins comprise a conserved GTPase domain and a C-terminal lipid-modified tail that is unique to each isoform. The GTPase domain is a 'switch' that regulates multiple signaling cascades that drive cell growth and proliferation when activated by binding GTP, and the signal is terminated by GTP hydrolysis. Oncogenic RAS mutations disrupt the GTPase cycle, leading to accumulation of the activated GTP-bound state and promoting proliferation. RAS is a key target in oncology, however it lacks classic druggable pockets and has been extremely challenging to target. RAS signaling has thus been targeted indirectly, by harnessing key downstream effectors as well as upstream regulators, or disrupting the proper membrane localization required for signaling, by inhibiting either lipid modification or 'carrier' proteins. As a small (20 kDa) protein with multiple conformers in dynamic equilibrium, RAS is an excellent candidate for NMR-driven characterization and screening for direct inhibitors. Several molecules have been discovered that bind RAS and stabilize shallow pockets through conformational selection, and recent compounds have achieved substantial improvements in affinity. NMR-derived insight into targeting the RAS-membrane interface has revealed a new strategy to enhance the potency of small molecules, while another approach has been development of peptidyl inhibitors that bind through large interfaces rather than deep pockets. Remarkable progress has been made with mutation-specific covalent inhibitors that target the thiol of a G12C mutant, and these are now in clinical trials. Here we review the history of RAS inhibitor development and highlight the utility of NMR and integrated biophysical approaches in RAS drug discovery. |
| Databáze: | OpenAIRE |
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