Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development

Ding, Qingjie; Zhang, Zhuming; Liu, Jin-Jun; Jiang, Nan; Zhang, Jing; Ross, Tina M.; Chu, Xin-Jie; Bartkovitz, David; Podlaski, Frank; Janson, Cheryl; Tovar, Christian; Filipovic, Zoran M.; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir T.; Graves, Bradford

doi:10.1021/jm400487c

Cited by 617Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerHeat shock proteins research

Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development

Ding, Qingjie, Zhang, Zhuming, Liu, Jin-Jun, Jiang, Nan, Zhang, Jing, Ross, Tina M., Chu, Xin-Jie, Bartkovitz, David +9 more·2013·Journal of Medicinal Chemistry

DOI 10.1021/jm400487c

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Abstract

Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

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RG-7388 (idasanutlin) is the first potent oral MDM2 protein inhibitor developed by Roche.
“RG-7388 (149), also known as idasanutlin, is the first potent oral MDM2 protein inhibitor developed by Roche.399”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [399]
RG-7388 can effectively activate the p53 pathway, induce wild type p53 expression, trigger cell cycle block or apoptosis, and inhibit tumor proliferation in neuroblastoma transplant tumor.
“With its exceptional activity and selectivity, RG-7388 can effectively activate the p53 pathway, induce wild type p53 expression, trigger cell cycle block or apoptosis, and inhibit tumor proliferation in neuroblastoma transplant tumor.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [399]
RG-7388's inhibitory activity (IC50 = 6 nM) is three times that of RG-7112 (IC50 = 18 nM).
“Notably, RG-7388’s inhibitory activity (IC50 = 6 nM) is three times that of RG-7112 (IC50 = 18 nM).399,400”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [399]
WB138 increases levels of both p53 and MDM2, consistent with previous reports on MDM2 inhibitors.
“WB138 increases the levels of both p53 and MDM2, which is consistent with the activity of previous reports on MDM2 inhibitors[28,32–36].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [34]
RG7388 binding activity to MDM2 reached 6 nM, antiproliferative activity against various tumor cells with high expression of wild-type p53 was approximately 300 nM, selectivity over p53 mutant tumor cells was greater than 100 times, oral bioavailability in mice reached 80%, half-life was 1.6 h, and metabolic stability was better than Compounds 1 and 2.
“The binding activity of RG7388 to MDM2 reached 6 nM, and the antiproliferative activity against various tumor cells with high expression of wild-type p53 was approximately 300 nM. The selectivity over p53 mutant tumor cells was greater than 100 times. The oral bioavailability in mice reached 80%, half-life was 1.6 h, and the metabolic stability was better than those of Compounds 1 and 2.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [29]

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Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development
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Authors: Ding, Q., Zhang, Z., Liu, J.-J., Jiang, N., Zhang, J., Ross, T. M., Chu, X.-J., Bartkovitz, D., Podlaski, F., Janson, C., Tovar, C., Filipovic, Z. M., Higgins, B., Glenn, K., Packman, K., Vassilev, L. T., & Graves, B.
Affiliations: F. Hoffmann-La Roche AG (CH)
Discovery Chemistry, ‡Discovery Technologies, §Discovery Oncology, ∥Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States
Corresponding author: Zhang, Zhuming
Graves, Bradford
ORCID: Ding, Qingjie
Zhang, Zhuming
Jiang, Nan
Zhang, Jing
Higgins, Brian
Glenn, Kelli
Packman, Kathryn
Vassilev, Lyubomir T.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2013-07-16
Volume: 56
Issue: 14
Pages: 5979-5983
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/jm400487c
OpenAlex: W1991167758
Cited by: 595
References: 35
Citations by year: 2026: 26 · 2025: 50 · 2024: 33 · 2023: 59 · 2022: 52 · 2021: 72 · 2020: 53 · 2019: 56 · 2018: 45 · 2017: 30 · 2016: 32 · 2015: 44 · 2014: 37 · 2013: 6
FWCI: 23.38
Type: journal article
Language: en
Open access: closed
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords: RG7388, RG7112, p53-MDM2 interaction, MDM2 inhibitors, p53 restoration, protein-protein interaction inhibitors, small molecule inhibitors, cancer therapy
MeSH terms: Animals, Antineoplastic Agents, Humans, Male, Mice, Inbred C57BL, Pyrrolidines, Tumor Suppressor Protein p53, Mice, Proto-Oncogene Proteins c-mdm2, Drug Discovery, para-Aminobenzoates

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Discovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development

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