Anti colorectal cancer activity and in silico studies of novel pyridine nortopsentin analog as cyclin dependent kinase 6 inhibitor | Scientific Reports

Nov 02, 2024

Scientific Reports volume 14, Article number: 26327 (2024) Cite this article

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Nortopsentins are a vital class of deep-sea sponge metabolites which can be used as leads for antitumor agents. Although their action has been studied in several diseases’ contexts, their cytotoxic activity against colorectal carcinoma has not yet been fully investigated. Therefore, a series of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridin-5-carbonitriles 4a–j (nortopsentin analogs) was investigated for their cytotoxic activity against colorectal carcinoma. The analog 4i showed the highest antitumor activity via inducing cell cycle arrest at G1 phase. Cell cycle arrest was induced due to expression downregulation of CDK2, CDK4, and CDK6. In addition, 4i suppressed the enzymatic activity of CDK6. The theoretical study of some basic quantum factors and the geometric shape of compound 4i proved that the compound is stable and a soft molecule, in which the EHOMO and ELUMO energies were negative and had a small ∆E gap. 4i also demonstrated a high potential for oral bioavailability due to its adherence to Lipinski’s rule of five. The molecular docking studies of 4i analog showed good binding mode with CDK6 active pocket through the formation of multiple interactions with its key amino acids.

Colorectal cancer is the third most common cancer type which is responsible for an enormous number of deaths reaching 881,000 deaths worldwide in 20181,2. Advancements in diagnostic measures led to its early detection, hence early treatment. The main treatment for colorectal cancer is endoscopic and surgical excision in addition to preoperative radiotherapy which are extremely invasive compared with small-molecule targeting therapy1. Since, the molecular basis for colorectal cancer development and its underlying causes have largely been identified3,4, the discovery of novel small molecules against colorectal cancer is inevitable. One of the main mechanisms for cancer development is cell cycle dysregulation. Cell cycle is a well-controlled process that requires multiple checkpoints in order to prevent uncontrolled cell division. Each phase of the cell cycle is regulated by a complex network of mechanisms to ensure the absence of any errors before they proceed to the following phase. Evading these controls leads to DNA damage accumulation and continuous cell division giving rise to cancerous cells5. Cyclin-dependent kinases (CDKs) are a family of enzymes that control cell cycle through interacting with different cyclins. Changes in CDKs activity regulate cell cycle entry, progression, and cell division6. Various cyclins interact with CDKs forming stable complexes leading to CDKs phosphorylation and activation7. Cyclin–CDK complexes in human network are composed of more than 20 CDKs and up to 30 distinct cyclin proteins8. The activation of these complexes is induced by several mitogenic signals and inhibited by cell-cycle checkpoints6. Therefore, CDKs are substantially highly expressed in cancer tissues compared with normal tissues and their dysregulation is closely associated with tumorigenesis9. The classical cell cycle CDKs are Cdk1, Cdk2, Cdk4, and Cdk6 which coordinate cell cycle progression. For the cell cycle to start, mitogenic signals induce the expression of the D-type cyclins that preferentially bind and activate both CDK4 and CDK6 leading to G1/S phase transition10,11,12. This activation of cyclinD-CDK4/6 complexes upregulates E-type cyclins which in turn bind to CKD2 forming a complex that is essential to further drive the transition from G1 triggering S phase13. CDK1 is another cyclin dependent kinase which is essential for cell cycle progression where it promotes the G2/M phase transition by binding to cyclin A, leading to mitotic entry14,15. Hence, CDKs have become attractive targets against different types of cancer such as breast cancer7 and solid tumors16. A wide variety of CDK inhibitors have been developed to suppress cell cycle progression17. For instance, inhibiting CDK4/6 hyperactivity using small molecules led to different potent antiproliferative agents against retinoblastoma (Rb)-positive tumor cells. These CDK4/6 inhibitors induced an exclusive G1 arrest, such as palbociclib, abemaciclib, ribociclib, and Trilaciclib11. Hence, developing inhibitors targeting CDK4/6 is considered a promising strategy for suppressing tumorigenesis.

The marine environment is a superb source of natural bioactive compounds, especially anti-tumor agents18,19. Nortopsentins A–D represents an important class of deep-sea sponge metabolites, useful as leads for antitumor agents20. Nortopsentins A–D (Fig. 1) are characterized by two indole units linked, through their position 3, by an imidazole core as a spacer which had been isolated from Spongosorites ruetzleri20. Several nortopsentin analogs have been designed where different heterocyclic rings replaced the imidazole ring of the natural compound. These analogs showed anti-proliferative activity21,22,23 where some of which inhibited CDK124,25,26. Figure 1 displays some examples of these analogs. The thiophene nortopsentin analog (I) was particularly effective against the leukemia subpanel (CCRF-CEM (GI50, MOLT-4, HL60 TB), and RPMI-8226) with GI50 values ranging from 0.34 to 3.54 μM21. On the other hand, the pyridine nortopsentin analog (bis(indolyl)-4-trifluoromethylpyridine, II) showed significant cytotoxic activity with IC50 values of 4.3 and 1.7 μM against P388 and A549 cell lines, respectively27. For CDK1, the thiazole nortopsentin analog (III) demonstrated antitumor activity against MCF7 cancer cell line via inhibiting CDK1 activity in vitro where the viable cells were trapped in G2/M phase24.

Chemical structures of natural nortopsentin A–D and its analogs.

Based on these findings, our present work aims to utilize the pyridine nortopsentin analogs we previously prepared28 to investigate their antitumor activity against several cancer cell lines. Next, we examined the anti-proliferative mechanism against the cancer cell lines affected by the most active analog. Moreover, we conducted an in-silico study including an analysis of certain basic quantum parameters, an analysis of the geometric shape, and drug-likeness (ADME). Finally, a molecular docking study was performed to elucidate the potential binding patterns of the active nortopsentin analog against the active pocket of CDK6.

Figure 2 illustrates the chemical pathway of our previous work for obtaining pyridine nortopsentin analogs (2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridin-5-carbonitriles (4a–j)28. Hence, we investigated their antitumor activity against several cancer cell lines.

Pyridine nortopsentin analogs (4a–j).

In order to determine the cytotoxic activity of nortopsentin analogs (4a–4j), their antitumor activity was measured against 60 different cell lines (Supplementary Table s1). The heatmap in Fig. 3 demonstrates the antitumor activity of all nortopsentin analogs against all tested cancer cell lines where the red color indicates higher tumor cells viability while the blue color indicates less tumor cells viability. The analog 4i exhibited the highest level of cytotoxic activity against almost all tumor cell lines. Colorectal cancer was one of the tumors against which 4i analog showed the highest cytotoxic activity, hence we focused on investigating 4i cytotoxic mechanism of action. Using the MTT assay test, the analog 4i showed IC50 in the nanomolar range (28.8 nM) compared with doxorubicin that showed IC50 of 10.11 µM. This demonstrates that 4i analog is a very potent cytotoxic compound against colorectal cancer.

Heatmap of nortopsentin analogs (4a–4j) demonstrating their effect on colorectal cancer cells viability.

4i analog was further investigated for its cytotoxic mechanism of action. To analyze the cell cycle changes induced by the 4i analog, colorectal cancer cells were treated with either 4i or DMSO as a control for 48 h and the cell were treated with PI for flow cytometric analysis. Figure 4a shows the histograms of both the control and 4i analog demonstrating PI signals at each phase. 4i histogram showed an increase in signal intensity at G1 phase. Moreover, the distribution of cells in each phase of the cell cycle was measured. As illustrated in Fig. 4b, 4i analog significantly induced cell cycle arrest at G1 phase (47.62%) compared with control cells (41.93%). Hence, 4i analog exerts its cytotoxic action against colorectal cancer via cell cycle arrest at G1 phase.

(a) Histograms of cell cycle phases using PI staining for FACS analysis. (b) Percentages of cells accumulation in all cell cycle phases induced by 4i analog versus control cells. Data are represented as the mean ± SD of three independent experiments (Fig. s1). Statistical analysis was conducted using one-way ANOVA followed by Bonferroni’s multiple comparison test; *p < 0.05, **p < 0.01, ***p < 0.001 compared to the control.

Cyclin dependent kinases are considered major key players in regulating the different phases of the cell cycle. CDK2, CDK4 and CDK6 are known to control the cell cycle transition from G1 to S phase. Since 4i analog induced cell cycle arrest at G-1 phase, we analyzed the expression of CDK2, CDK4, and CDK6 genes. 4i analog was able to significantly suppress the expression of all three CDK genes responsible for regulating the G1 phase as shown in Fig. 5. Such a decrease explains 4i analog’s ability to inhibit colorectal carcinoma growth. Moreover, we measured the activity of the three CDK enzymes along with their activating cyclin subunits, CDK2/cyclin E1, CDK4/cyclin D3 and CDK6/D3. As shown in Table 1, 4i analog significantly decreased the activity of CDK6/D3 where it’s IC50 (0.098 µM) compared with the positive control staurosporine which had IC50 of 0.277 µM. However, 4i analog did not induce the same significant decrease in the activity of the other two enzymes. IC50 of CDK2/cyclin E1 was 0.658 µM compared with the positive control staurosporine with IC50 of 0.035 µM, while IC50 of CDK4/cyclin D3 was 0.265 µM compared with the positive control palbociclib with IC50 of 0.034 µM. Therefore, 4i mainly inhibited colorectal carcinoma growth in CDK 6/cyclin D3 dependent manner.

Relative gene expression of CDK2, CDK4 and CDK6 induced by 4i analog. Data are represented as mean ± SD of three individual experiments. Statistical analysis was done using Mann Whitney test; *p < 0.05 compared to the control.

The molecular modeling (as a theoretical method) has been done using the Gaussian09 program29 to analyze certain basic quantum parameters as well as the geometric shape of compound 4i. Global interaction parameters were analyzed according to previously reported30 including, the highest occupied molecular orbital (EHOMO), the lowest unoccupied molecular orbital (ELUMO), energy gap (ΔE), dipole moment (µ), softness (σ), global softness (S), global electrophilicity index (ω), global hardness (η), absolute softness (S), the fraction of electrons transferred (∆N), the total energy (TE), electronegativity (χ), ionization potential (I), and electron affinity (A). The results are given in Table 2.

Figure 6 displays the LUMO and HOMO molecular orbital representations of 4i. The result from Fig. 6 showed that the HOMO was mainly distributed over the pyridine moiety and the CN functional group, with some density above the phenyl ring located at the para-position to the pyridine ring. The LUMO densities were distributed on the pyrrole moiety with its substituents (p-(N,N-dimethyl)phenyl) and CN function group. The result from Table 2 showed that the energies of HOMO and LUMO are negative, indicating that 4i is stable. In addition, it has been proven that the value of EHOMO is higher than the value of ELUMO level.

LUMO and HOMO patterns of compound 4i.

The total atomic charge distribution was estimated using charges population analysis with optimized geometry, with the results presented in Tables s2–s5 and Fig. 7a while Fig. 7b shows the numbering scheme of 4i.

(a) The charge distribution of 4i; (b) The numbering scheme for compound 4i structure.

The drug-likeness of compound 4i according to Lipinski’s rule of five and some predictions of physicochemical and pharmacokinetic (ADME) (Table 3) using the free tool Swiss-ADME31, compound 4i could have a high chance of oral bioavailability.

The molecular docking study of compound 4i towards the target crystal structures of CDK6 binding site of PDBs: 1XO2, 2EUF, 2F2C, 3NUX, and 4EZ5 with inhibitors FSE, LQQ, AP9, 3NV, and 0RS, respectively, was achieved via PyRx tools Autodock Vina (version 1.1.2)32. The docking results are shown in (Figs. 8) and supplementary (Table s6, Figs. s2–s6).

(A) The 2D interactions of 4i inside the active pockets of the target crystal structures of CDK6 of PDBs: (a) 1XO2, (b) 2EUF, (c) 2F2C, (d) 3NUX, and (e) 4EZ5; (B) The 3D interactions of 4i inside the active pockets of the target crystal structures of CDK6 of PDBs: (a) 1XO2, (b) 2EUF, (c) 2F2C, (d) 3NUX, and (e) 4EZ5.

Interestingly, it has been observed that the interaction of 4i against the CDK6 crystal structures consists of some remarkable notes. Where 4i is identical with each native ligand in many bonds with the same active amino acid of the CDK6 crystal structure. For 1XO2, compound 4i showed conventional H-bond, C–H bond, Pi-alkyl, and Pi-sigma interactions with the amino acids, GLU21, ASP163, VAL27, GLY22 of the active pocket of 1XO2 as the native ligand (FSE) (Fig. 8a). Whereas 4i gets engaged with the active amino acids ILE19, ALA41, and LEU125 of the active pocket of (PDB: 2EUF) via Pi-alkyl and Pi-sigma interactions as the native ligand (LQQ) (Fig. 8b). On the other hand, compound 4i displayed Pi-alkyl and Pi-sigma interactions with the active pocket of CDK6 (2F2C) via amino acids, VAL77, ALA162, and ASP104 as native ligand (AP9) (Fig. 8c). For the active pocket of 3NUX, compound 4i showed Pi-anion interaction with active amino acid ASP104 as the native ligand 3NV (Fig. 8d). Compound 4i affinity towards the active pocket of 4EZ5 showed that 4i was the most fortunate in being associated with the active amino acids ASP104, GLN49, VAL27, ILE19, LEU152, and LYS43 as the native ligand 0RS via conventional H-bond, C-H bond, Pi-alkyl, Pi-sigma, and unfavorable D-D interactions (Fig. 8e).

Nortopsentins are groups of sponge metabolites which are considered promising lead compounds for broad spectrum of biological properties. Nortopsentins exert cytotoxic activity against a broad range of tumors, such as breast cancer33, non-small cell lung cancer21, leukemia20, and liver cancer34. Cell cycle arrest is one of the main antiproliferative mechanisms of many antitumor agents6. Cyclin dependent kinases are key enzymes that orchestrate the cell cycle process and their dysregulation is a hallmark of several types of tumors10. To evaluate the cytotoxic activity of nortopsentin analogs (4a–4j), their antitumor activity was measured against 60 different cancer cell lines, including breast cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, etc. The analog 4i exhibited the highest level of cytotoxic activity against almost all tumor cell lines, with the highest antitumor activity against colorectal carcinoma. Therefore, we have investigated the effect of 4i analog on the cell cycle of colorectal carcinoma. Our data showed that 4i significantly induced cell cycle arrest in colorectal carcinoma at G1 phase. This is in alignment with another study that shows two nortopsentin analogs, namely thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, with the ability to induce cell cycle arrest at G1 phase22. CDK2, CDK4, and CDK6 with their corresponding cyclins control cells transition from G1 to the S phase during the cell cycle10,12. Hence, the synthesis of new nortopsentin analogs which act as CDK enzymes inhibitors is a promising strategy for developing new anticancer therapeutics35,36. Several studies show the ability of different nortopsentin analogs to inhibit CDK124,25, CDK237 and CDK438. Our results showed that 4i affected all three CDK enzymes that are responsible for G1 phase transition. It suppressed the expression of CDK2, CDK4 and CDK6. Moreover, it downregulated CDK6 enzymatic activity compared with the control, staurosporine. Surprisingly, there are no data about other nortopsentin analogs which target CDK6. Thus, 4i is the first nortopsentin analog to inhibit CDK6 at both transcriptional and enzymatic activity levels. Fundamental quantum parameters and geometry of compound 4i were performed to correlate the activity of 4i to induce the cell cycle arrest in colorectal cancer with molecular orbital (MO) energy levels of 4i. The EHOMO and ELUMO molecular orbitals and their energy gap ΔE help determine the kinetic stability and chemical reactivity of the molecule when it interacts with the target enzyme or protein29. The result showed that the energies of HOMO and LUMO were negative, which indicates 4i is stable. An increase in the value of the EHOMO level and a decrease in the value of the ELUMO level show an increment in the binding ability between 4i and the target enzyme active pocket. As ΔE decreases, the reactivity of the molecule increases, leading to a better inhibition efficiency39. A molecule with a low energy gap is more polarizable and is generally associated to the high chemical activity and low kinetic stability, such molecule is called “soft molecule”39. Our results indicated that 4i is a soft molecule that has a small ΔE gap (0.07031 eV). High values of the ionization energy (I) evidence the chemical inertness and strong stability, whereas small ionization energy denotes the high reactivity of the atoms and molecules40. Our results showed that compound 4i had low ionization energy (0.17307 eV) indicating its activity. 4i also showed high chances of oral bioavailability due to its compatibility with Lipinski’s rule of five. Moreover, to correlate the in vitro CDK6 data for the present analog (4i), the target crystal structures of CDK6 binding site of PDBs: 1XO2, 2EUF, 2F2C, 3NUX, and 4EZ5 with the inhibitors FSE, LQQ, AP9, 3NV, and 0RS, respectively was employed using the molecular docking study. Our results indicated that 4i was superimposable to the native ligands. In addition, it showed good binding mode with the active pocket through the formation of multiple interactions with the key amino acids of CDK6 in a similar manner as native ligands. Also, it revealed a good binding energies towards the binding site for all CDK6 crystal structures with values higher than the native ligands. Hence, 4i analog is the first nortopsentin analog that acts as antitumor agent against colorectal carcinoma via inhibiting CDK6 at both transcriptional and enzymatic activity levels. Despite the struggle to find explicit structure–activity relationships from the biological data, some conclusions can still be considered. First, nortopsintine with no substitution (R = H) or substituted with a, halogen (R = Br, Cl, F); b, (R = OMe, di,-OMe, tri-OMe); c, (R = NO2); d, (R = OH) doesn’t show antiproliferative activity. Second, only nortopsintine substituted with N(CH3)2 (nitrogen groups with lone pairs representing an activating group) enhanced antiproliferative activity against most cancer cell lines under study. This finding is consistent with previous studies that reported that the presence of an electron-donating group on the phenyl ring is largely preferred over the presence of an electron-withdrawing group, negatively affecting cytotoxic efficacy41.

HCT-116 (colon cancer cell line) was obtained from the American Type Culture Collection (ATCC). The cancer cell line was grown in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), penicillin/streptomycin (100 U/mL and 100 μg/mL, respectively) and 2 mM l-glutamine. The cells were maintained at 37 °C in 5% CO2.

The cytotoxic activity of nortopsintin analogs (4a–4j) was determined by the national cancer institute (NCI, Bethesda, Maryland, USA) against 60 different cancer cell lines at a single concentration of (10−5 M). For the determination of IC50 value, we used MTT assay kit (Sigma) according to the manufacturer’s protocol. HCT-116 cells were seeded into a 96-well plate at a concentration of 20,000 cells/well. After 24 h, the media was aspirated and replaced with serum-free media containing serial dilutions of the 4i compound. The cells were treated for 48 h in triplicates. 0.5% dimethyl sulfoxide (DMSO) was used as negative control and staurosporine was used as positive control. The percentage of cytotoxicity was calculated using the following equation: % Cytotoxicity = [1 − (AVx/AVNC)] × 100.

Where, AVx denotes the average absorbance of the sample and AVNC denotes the average absorbance of the negative control. The absorbance was measured at 570 nm with reference at 690 nm.

The cells were seeded in a six-well plate at a concentration of 3 × 105 cells/well. After a 24 h incubation, the IC50 dose of active compound 4i was applied to each well for 48 h. The cells were collected and centrifuged at 2500 rpm for 15 min at 4 °C. The total RNA isolation kit (RNeasy extraction kit—QIAGEN) was used to isolate RNA according to the manufacturer’s instructions.

Gene expression analysis by quantitative real-time PCR. The levels of gene expression of CDK2, CDK4 and CDK6 were determined using iScript One-Step RT-PCR kit with SYBR Green (BIORAD) according to the manufacturer protocol. The sequences of the used primers are illustrated in Table 4. The genes expression was normalized to GAPDH as the housekeeping gene. The protocol used for cDNA synthesis was: 10 min at 50 °C, iScript Reverse transcriptase inactivation: 5 min at 95 °C and PCR cycling and detection (30 to 45 cycles): 10 s at 95 °C and 30 s at 55 °C to 60 °C.

Briefly, HCT116 cells were treated with 4i compound’s IC50 for 48 h. Then, the cells were fixed in cold 70% ethanol solution for 2 h at 4 °C and centrifuged at 800 g for 5 min. The ethanol solution was removed. PBS was used to wash the cells twice. DNA was stained with 1 µg/mL propidium iodide (PI) solution (Sigma-Aldrich, St. Louis, MO, USA), supplemented with 100 µg/mL RNase A (Roche, Basel, Switzerland) for 30 min in the dark at 37 °C. After centrifugation, the cells were suspended in phosphate buffer solution and the fluorescence was measured using flow cytometry by FACSCalibur (BD Biosciences, Mountain View, CA). The data were analyzed using the CellQuest software (BD Biosciences).

HCT-116 cells were treated with 4i or the control inhibitors: palbociclib and staurosporine for 48 h in triplicates. ADP-Glo™ Kinase Assay kit (Promega, USA) was used for the enzymatic activity analysis according to the manufacturer’s instructions. In brief, to each well we added 1 μl of inhibitor, 2 μl of each cyclin dependent kinase enzymes, and 2 μl of substrate/ATP mix and incubated at room temperature for 60 min. After that 5 μl of ADP‐Glo™ reagent was added and incubated at room temperature for 40 min. 10 μl of kinase detection reagent was added and incubated at room temperature for 30 min, then the luminescence was measured.

With Gaussian09 software, the ideal structural geometry of compound 4i was calculated using the ground state, DFT, B3LYP, and 3-211G. Gaussian files were shown using the molecular visualization software Gauss View42. The DFT/B3LYP quantum chemical parameters were computed using HOMO–LUMO energies that agreed with the numerical pattern shown in the gas phase compounds view. In optimized structures, significant bond lengths, bond angles, dihedral angles, charges, and excitation energy for coordinating groups were also calculated.

Molecular docking studies of the active compound 4i against the crystal structures of five CDK6 targets were performed using PyRx tools Autodock Vina (version 1.1.2)32. The crystal structures of CDK6 complexed with the inhibitors were downloaded from RCSB Protein Data Bank (accessed on 29-6-2023). The molecular interactions and binding modes of the top poses were visually examined using BIOVIA Discovery Studio 2021.

Comparisons between multiple treatments were made by either, Student t-test, one-way or two-way ANOVA, followed by Dunnett’s multiple comparison test; *p < 0.05, **p < 0.01, ***p < 0.001 were considered to be a significant difference. GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA) was used for statistical analysis and plotting the graphs.

Nortopsentin analogs 4a–j were screened against 60 different cancer cell lines. 4i analog exhibited the highest level of cytotoxic activity against almost all tumor cell lines including colorectal carcinoma. 4i induced cell cycle arrest in colorectal carcinoma through downregulating the expression of CDK2, CDK4 and CDK6. In addition, 4i decreased the enzymatic activity of CDK6 compared with the control staurosporine. The theoretical study of some basic quantum factors and the geometric shape of compound 4i showed that it’s a stable and soft molecule. It showed negative EHOMO and ELUMO energies and a small ∆E gap. 4i has also revealed high potential for oral bioavailability due to its compatibility with Lipinski’s rule of five. Furthermore, 4i showed good binding mode with CDK6 active pockets through the formation of multiple interactions with the key amino acids in a similar manner as native ligands. Hence, 4i analog is a promising candidate for further preclinical studies against colorectal carcinoma.

All data generated or analyzed during this study are included in this published article and its supplementary information file.

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Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt

Heba Abdelmegeed, Heba M. Abo-Salem & Eslam R. El-Sawy

Green Chemistry Department, National Research Centre, Dokki, 12622, Giza, Egypt

Ehab M. Zayed

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H.A. contributed to in vitro biochemical analysis, all biological data interpretation, and statistical analysis; E.R.E.-S. & H.M.A.-S. Designed, and prepared nortopsentin analogs; E.M.Z. Performed molecular modeling study; E.R.E.-S. Performed the molecular docking; H.A., E.R.E.-S contributed to writing and editing the manuscript

Correspondence to Eslam R. El-Sawy.

The authors declare no competing interests.

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Abdelmegeed, H., Abo-Salem, H.M., Zayed, E.M. et al. Anti colorectal cancer activity and in silico studies of novel pyridine nortopsentin analog as cyclin dependent kinase 6 inhibitor. Sci Rep 14, 26327 (2024). https://doi.org/10.1038/s41598-024-75411-3

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Received: 24 June 2024

Accepted: 04 October 2024

Published: 01 November 2024

DOI: https://doi.org/10.1038/s41598-024-75411-3

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