Small-molecule correctors and stabilizers to target p53

Fallatah, Maryam M.J.; Law, Fiona V.; Chow, Warren A.; Kaiser, Peter

doi:10.1016/j.tips.2023.02.007

Cited by 44Cancer-related Molecular PathwaysHeat shock proteins researchPI3K/AKT/mTOR signaling in cancer

Small-molecule correctors and stabilizers to target p53

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Fallatah, Maryam M.J., Law, Fiona V., Chow, Warren A., Kaiser, Peter·2023·Trends in Pharmacological Sciences

DOI 10.1016/j.tips.2023.02.007PMC PMC10511064

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Abstract

The tumor suppressor p53 is the most frequently mutated protein in human cancer and tops the list of high-value precision oncology targets. p53 prevents initiation and progression of cancer by inducing cell-cycle arrest and various forms of cell death. Tumors have thus evolved ways to inactivate p53, mainly by TP53 mutations or by hyperactive p53 degradation. This review focuses on two types of p53 targeting compounds, MDM2 antagonists and mutant p53 correctors. MDM2 inhibitors prevent p53 protein degradation, while correctors restore tumor suppressor activity of p53 mutants by enhancing thermodynamic stability. Herein we explore both novel and repurposed p53 targeting compounds, discuss their mode of action, and examine the challenges in advancing them to the clinic.

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Small-molecule MDM2 inhibitors are the most clinically advanced therapeutics targeting this pathway, and there are numerous clinical trials evaluating this class of drugs across various malignancies.
“Small-molecule MDM2 inhibitors are the most clinically advanced therapeutics targeting this pathway, and there are numerous clinical trials evaluating this class of drugs across various malignancies.2,3”
From Pharmacokinetic-pharmacodynamic-efficacy modeling of the MDM2 inhibitor brigimadlin in glioblastoma patient-derived xenografts (2026) · cites this paper as [2]
The section “Small molecules that block p53 degradation (MDM2 antagonists)” describes clinical evaluations of multiple MDM2 inhibitors in liposarcoma, hematological malignancies, and other solid tumors. It does not establish the comparative claim that they are the most clinically advanced therapeutics targeting the p53 pathway; it also notes that clinical efficacy has not met expectations. Page numbers were not provided in our copy. (LLM, conf=0.81)
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Preclinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH–Wild-type Glioblastoma
Vaubel, R. A., Zhang, W., Oh, J.-H., Mladek, A. C., Pasa, T. I., Gantchev, J. K., Waller, K. L., Baquer, G., Stopka, S. A., Regan, M. S., et al. (2025) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-25-0244 · Cited by 2 · see citing works
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Vaubel, R. A., Zhang, W., Karbhari, N., Oh, J.-H., Waller, K. L., Mladek, A., Jain, S., Burgenske, D. M., Decker, P. A., Kosel, M. L., et al. (2026) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdaf259

Authors: Fallatah, M. M. J., Law, F. V., Chow, W. A., & Kaiser, P.
Affiliations: University of California, Irvine (US)
Corresponding author: Kaiser, Peter
ORCID: Fallatah, Maryam M.J.
Chow, Warren A.
Kaiser, Peter
Venue: Trends in Pharmacological Sciences
Publisher: Elsevier BV
Published: 2023-05
Volume: 44
Issue: 5
Pages: 274-289
ISSN: 0165-6147 (ISSN-L)
DOI: 10.1016/j.tips.2023.02.007
PMC: PMC10511064
OpenAlex: W4353098259
Cited by: 44
References: 104
Citations by year: 2026: 18 · 2025: 11 · 2024: 12 · 2023: 3
FWCI: 1.42
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 348 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Trends in Pharmacological Sciences (acceptedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institutes of Health (R35GM148350, R21CA267495-A1, US20150307519 A1, US20160193214 A1)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: p53, MDM2 inhibitors, p53 stabilization, TP53 mutation, p53 degradation, small molecule drugs, precision oncology, drug repurposing, cancer therapy
MeSH terms: Antineoplastic Agents, Humans, Neoplasms, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2, Precision Medicine

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Small-molecule correctors and stabilizers to target p53

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