title: Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.
abstract: The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Zhuming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Chu
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bartkovitz
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Prabha
authors.initials: P
authors.lastname: Karnachi
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Zoran M
authors.initials: ZM
authors.lastname: Filipovic
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.affiliation: Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, 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 Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
keywords: MDM2; apoptosis; cancer; p53; small molecule; wild-type