Multivalent Small-Molecule Pan-RAS Inhibitors

• Published in: Cell Vol. 168; no. 5; pp. 878 - 889.e29
• Main Authors: Welsch, Matthew E., Kaplan, Anna, Chambers, Jennifer M., Stokes, Michael E., Bos, Pieter H., Zask, Arie, Zhang, Yan, Sanchez-Martin, Marta, Badgley, Michael A., Huang, Christine S., Tran, Timothy H., Akkiraju, Hemanth, Brown, Lewis M., Nandakumar, Renu, Cremers, Serge, Yang, Wan Seok, Tong, Liang, Olive, Kenneth P., Ferrando, Adolfo, Stockwell, Brent R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.02.2017
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Calorimetry; cancer; Cell Line; chemical biology; drug design; Fibroblasts - metabolism; GTPase; Heterografts; Hras; Humans; Kras; Mice; Molecular Targeted Therapy; multivalent; Neoplasm Transplantation; Neoplasms - drug therapy; Nras; Pancreatic Neoplasms - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - chemistry; Ras; Signal Transduction; small molecule; Small Molecule Libraries; small molecule; Nras; chemical biology; Ras; drug design; multivalent; Kras; cancer; GTPase; Hras
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.02.006

Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins. [Display omitted] •Identification of small molecule ligands targeting adjacent sites on RAS proteins•Compound 3144 bound to KRASG12D as shown by MST, ITC, and NMR•Compound 3144 exhibited cellular lethality, partially dependent on RAS expression•Compound 3144 inhibited tumor growth and RAS signaling in mouse cancer models A computational design approach yields multivalent pan-RAS inhibitors.