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. 2024 Apr;28(8):e18272.
doi: 10.1111/jcmm.18272.

Development, synthesis and validation of improved c-Myc/Max inhibitors

Sümbül Yıldırım  1   2   3 , Fatih Kocabaş  1   2 , Arif Mermer  4   5   6
Affiliations

Development, synthesis and validation of improved c-Myc/Max inhibitors

Sümbül Yıldırım et al. J Cell Mol Med. 2024 Apr.

Abstract

The pathophysiological foundations of various diseases are often subject to alteration through the utilization of small compounds, rendering them invaluable tools for the exploration and advancement of novel therapeutic strategies. Within the scope of this study, we meticulously curated a diverse library of novel small compounds meticulously designed to specifically target the c-Myc/Max complex. We conducted in vitro examinations of novel c-Myc inhibitors across a spectrum of cancer cell lines, including PANC1 (pancreatic adenocarcinoma), MCF7 (breast carcinoma), DU-145 (prostate carcinoma), and A549 (lung cancer). The initial analysis involved a 25 μM dose, which enabled the identification of potent anticancer compounds effective against a variety of tumour types. We identified c-Myc inhibitors with remarkable potency, featuring IC50 values as low as 1.6 μM and up to 40 times more effective than the reference molecule in diminishing cancer cell viability. Notably, c-Myc-i7 exhibited exceptional selectivity, displaying 37-fold and 59-fold preference for targeting prostate and breast cancers, respectively, over healthy cells. Additionally, we constructed drug-likeness models. This study underscores the potential for in vitro investigations of various tumour types using novel c-Myc inhibitors to yield ground-breaking and efficacious anticancer compounds.

Keywords: Max; anti‐cancer; c‐Myc; rhodanine; ultrasonication.

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Conflict of interest statement

The authors declare that they have no conflicts of interest to disclose.

Figures

SCHEME 1
SCHEME 1
Design of novel rhodanine derivatives.
SCHEME 2
SCHEME 2
One‐pot four‐component synthesis of rhodanine derivatives.
FIGURE 1
FIGURE 1
Analysis of novel c‐Myc derivatives in pathologically distinct cancers. Cell viability post treatment with 25 μM of novel c‐Myc inhibitors (c‐Myc‐i) in (A) A549 lung cancer, (B) Panc1 pancreatic cancer, (C) Du‐145 prostate cancer, (D) MCF7 breast cancer, and (E) human dermal fibroblasts. (F) Fold reduction in cancer cell viability post c‐Myc‐i treatments compared to DMSO control. n = 3.
FIGURE 2
FIGURE 2
Determination of IC50 values in A549 cells post c‐Myc‐i treatments. IC50 curve of (A) c‐Myc‐i7, (B) c‐Myc‐i8, (C) c‐Myc‐i10, and (D) 10058‐F4. (E) Quantification of IC50 values.
FIGURE 3
FIGURE 3
Determination of IC50 values in DU‐145 cells post c‐Myc‐i treatments. IC50 curve of (A) c‐Myc‐i7, (B) c‐Myc‐i8, (C) c‐Myc‐i10 and (D) 10058‐F4. (E) Quantification of IC50 values.
FIGURE 4
FIGURE 4
Determination of IC50 values in MCF7 cells post c‐Myc‐i treatments. IC50 curve of (A) c‐Myc‐i7, (B) c‐Myc‐i8, (C) c‐Myc‐i10, and (D) 10058‐F4. (E) Quantification of IC50 values.
FIGURE 5
FIGURE 5
Determination of IC50 values in Panc1 cells post c‐Myc‐i treatments. IC50 curve of (A) c‐Myc‐i7, (B) c‐Myc‐i8, (C) c‐Myc‐i10, and (D) 10058‐F4. (E) Quantification of IC50 values.
FIGURE 6
FIGURE 6
Apoptosis analysis of MCF7 Cells. MCF7 cells are treated with 2 μM of 10058‐F4 and c‐Myc‐i7 and tested for their apoptotic effect. (A) Apoptosis flow cytometry plots. (B) Quantification of early apoptotic, late apoptotic and necrotic cells.
FIGURE 7
FIGURE 7
Apoptosis analysis of DU145 Cells. DU145 cells are treated with 2 μM of 10058‐F4 and c‐Myc‐i7 and tested for their apoptotic effect. (A) Apoptosis flow cytometry plots. (B) Quantification of early apoptotic, late apoptotic and necrotic cells.
FIGURE 8
FIGURE 8
Cell cycle analysis of MCF7 cells. MCF7 cells are treated with 10058‐F4 and c‐Myc‐i7 and tested for their effect in the cell cycle. (A) Cell cycle flow cytometry plots. (B) Quantification of cells in G0‐G1, S and G2‐M phases of cell cycle.
FIGURE 9
FIGURE 9
Cell cycle analysis of DU145 Cells. DU145 cells are treated with 10058‐F4 and c‐Myc‐i7 and tested for their effect in the cell cycle. (A) Cell cycle flow cytometry plots. (B) Quantification of cells in G0‐G1, S and G2‐M phases of cell cycle.
FIGURE 10
FIGURE 10
Molecular docking and structural clustering of compounds. (A) Grid box and docking parameters used in the study. (B) Calculated binding affinities for compounds in the c‐Myc/Max DNA binding pocket (DBD). (C) Structural clustering of compounds based on the Soergel distance. (D) Docking pose of c‐Myc‐i7 in the c‐Myc/Max DBD pocket.
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