title: Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.
abstract: The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Binh
authors.initials: B
authors.lastname: Vu
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Wovkulich
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Pizzolato
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Allen
authors.initials: A
authors.lastname: Lovey
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Kelli
authors.initials: K
authors.lastname: Glenn
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Lyubomir
authors.initials: L
authors.lastname: Vassilev
authors.affiliation: Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
keywords: MDM2; RG7112; cancer; p53; protein−protein interaction