Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells

Abstract

Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding K i values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.

Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity

“…Therefore, modulation of multiple related targets to generate superior efficacy by hybrid molecule (single compound) is highly desirable. Our recent works and other studies have successfully demonstrated the effectiveness of MDM2-based dual inhibitors, like MDM2-GPX4, MDM2-CDK4, MDM2-XIAP, MDM2-MDM4, and so on (56)(57)(58)(59)(60)(61)(62)(63).…”

Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein–Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy

“…Previously, we have reported that 15 , a RG7388 derived compound, effectively inhibited MDM2-p53 interaction with K i value of 1.1 nM as well as MDM4/p53 interaction with a relatively weaker K i value of 0.64 μM. In cancer cells harboring wild-type p53, 15 promoted upregulation of p53 and its target genes, arrested cell cycle progression, and induced apoptosis.…”

“…Similar to the synthesis of 17e , 18d (219 mg, 0.32 mmol), DIEA (209 mg, 1.62 mmol), diphenylphosphinyl chloride (229 mg, 0.97 mmol), methyl-4-amino-3-methoxybenzoate (235 mg, 1.295 mmol), and piperidine (0.4 mL) were used. Upon HPLC purification, a TFA salt of 18e was obtained as a white solid (62 mg, 27%).…”

“…Upon HPLC purification, a TFA salt of the title compound 49 was obtained as a white solid (15.4 mg, 71%). 1 H NMR (400 MHz, Methanol-d 4 ): δ 8.21 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.47−7.39 (m, 3H), 7.34 (dd, J = 8.1, 1.5 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 8.0, 1.9 Hz, 1H), 6.49 (d, J = 1.8 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.40 (d, J = 10.4 Hz, 1H), 4.13−3.98 (m, 1H), 3.80 (s, 3H), 3.74 (d, J = 10.9 Hz, 1H), 3.56 (d, J = 10.9 Hz, 1H), 2.92 (s, 3H), 1.86−1 64. (m, 2H), 0.94 (s, 9H).…”

A Domino Radical Amidation/Semipinacol Approach to All‐Carbon Quaternary Centers Bearing an Aminomethyl Group

“…Arguably, the most common method used for accessing this motif is via reduction of the corresponding nitrile [6,7] . However, the nitriles are typically prepared via alkylation reactions involving toxic alkyl halides.…”