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Article

Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells

by
Rati Lama
1,†,
Samuel L. Galster
2,†,
Chao Xu
1,
Luke W. Davison
2,
Sherry R. Chemler
2,* and
Xinjiang Wang
1,*
1
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
2
Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2022, 27(22), 7665; https://doi.org/10.3390/molecules27227665
Submission received: 5 October 2022 / Revised: 31 October 2022 / Accepted: 3 November 2022 / Published: 8 November 2022
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)
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Abstract

MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis independent of p53. Despite the importance of the MDM2 RING domain in p53 regulation and cancer development, small molecule inhibitors targeting the E3 ligase activity of MDM2-MDM4 are poorly explored. Here, we describe the synthesis and characterization of quinolinol derivatives for the identification of analogs that are capable of targeting the MDM2-MDM4 heterodimer E3 ligase and inducing apoptosis in cells. The structure-activity-relationship (SAR) study identified structural moieties critical for the inhibitory effects toward MDM2-MDM4 E3 ligase, the targeted degradation of MDM4 and FTH1 in cells, and anti-proliferation activity. Lead optimization led to the development of compound MMRi71 with improved activity. In addition to accumulating p53 proteins in wt-p53 bearing cancer cells as expected of any MDM2 inhibitors, MMRi71 effectively kills p53-null leukemia cells, an activity that conventional MDM2-p53 disrupting inhibitors lack. This study provides a prototype structure for developing MDM4/FTH1 dual-targeting inhibitors as potential cancer therapeutics.
Keywords: MMRi; quinolinol; MDM4; E3 ligase; p53; ubiquitination; FTH1; apoptosis; leukemia MMRi; quinolinol; MDM4; E3 ligase; p53; ubiquitination; FTH1; apoptosis; leukemia
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MDPI and ACS Style

Lama, R.; Galster, S.L.; Xu, C.; Davison, L.W.; Chemler, S.R.; Wang, X. Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells. Molecules 2022, 27, 7665. https://doi.org/10.3390/molecules27227665

AMA Style

Lama R, Galster SL, Xu C, Davison LW, Chemler SR, Wang X. Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells. Molecules. 2022; 27(22):7665. https://doi.org/10.3390/molecules27227665

Chicago/Turabian Style

Lama, Rati, Samuel L. Galster, Chao Xu, Luke W. Davison, Sherry R. Chemler, and Xinjiang Wang. 2022. "Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells" Molecules 27, no. 22: 7665. https://doi.org/10.3390/molecules27227665

APA Style

Lama, R., Galster, S. L., Xu, C., Davison, L. W., Chemler, S. R., & Wang, X. (2022). Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells. Molecules, 27(22), 7665. https://doi.org/10.3390/molecules27227665

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