title: Multivalent Small-Molecule Pan-RAS Inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Welsch
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaplan
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Chambers
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stokes
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Bos
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.affiliation: Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Martin
authors.affiliation: Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Division of Digestive and Liver Diseases in the Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Badgley
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Tran
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY 10027, USA.
authors.forename: Hemanth
authors.initials: H
authors.lastname: Akkiraju
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY 10027, USA.
authors.forename: Lewis M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Nandakumar
authors.affiliation: Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Department of Biological Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Division of Digestive and Liver Diseases in the Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Olive
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.affiliation: Department of Chemistry, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002151:Calorimetry; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015398:Signal Transduction; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D054852:Small Molecule Libraries; D016283:Proto-Oncogene Proteins p21(ras)
keywords: GTPase; Hras; Kras; Nras; Ras; cancer; chemical biology; drug design; multivalent; small molecule