title: Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.
abstract: The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: zzhang85@its.jnj.com.
authors.forename: Zhuming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Chu
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bartkovitz
authors.affiliation: Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Kin-Chun
authors.initials: KC
authors.lastname: Luk
authors.affiliation: Discovery Technologies, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Janson
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Zoran M
authors.initials: ZM
authors.lastname: Filipovic
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.affiliation: Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Kelli
authors.initials: K
authors.lastname: Glenn
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
authors.affiliation: Discovery Technologies, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: bjgraves101@gmail.com.
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D048288:Imidazolines / Q000737:chemistry; D007211:Indoles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D054836:Indolizidines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry; D013141:Spiro Compounds / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D062366:para-Aminobenzoates / Q000737:chemistry
chemical_list: D048288:Imidazolines; D007211:Indoles; D054836:Indolizidines; D011759:Pyrrolidines; C579783:RG7112; C586849:RG7388; C000600870:RO8994; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D062366:para-Aminobenzoates; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Apoptosis; Cancer; MDM2; Protein–protein interaction; p53