Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 25, Issue 19, 2025

Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine protein kinase involved in regulating key cellular processes, including cell cycle progression, apoptosis, embryonic development, spliceosome assembly, and gene expression. Notably, MELK is overexpressed in Triple-Negative Breast Cancer (TNBC), an aggressive malignancy associated with poor prognosis, high drug resistance, and limited treatment options. Given its critical role in TNBC pathogenesis, MELK has emerged as a potential biomarker and therapeutic target. This review explores the molecular functions of MELK, its involvement in oncogenic signaling pathways, and the development of MELK-targeting small-molecule inhibitors.

A comprehensive literature review was conducted to evaluate current knowledge on MELK, including its molecular functions, interactions within signaling pathways, role in TNBC progression, and potential as a therapeutic target. Relevant databases, including PubMed, Web of Science, Embase, and Scopus, were searched for studies related to MELK expression, signaling mechanisms, and experimental therapeutic approaches.

MELK plays a central role in oncogenic signaling pathways that drive TNBC proliferation and survival. Preclinical studies have demonstrated that MELK inhibition can suppress TNBC cell growth and enhance chemotherapy efficacy. Several small-molecule inhibitors targeting MELK have shown promising anti-tumor activity in preclinical models. However, challenges remain in translating these findings into clinical applications due to drug specificity limitations and resistance mechanisms.

MELK is a promising biomarker and therapeutic target in TNBC. However, further research is required to refine MELK inhibitors, enhance clinical efficacy, and overcome drug resistance mechanisms. Targeting MELK could offer a novel therapeutic strategy to improve TNBC treatment outcomes.

1,4-Naphthoquinone and its derivatives are recognized for their potent anticancer effects, establishing this pharmacophore as a key focus in cancer research. Their potential to modulate cellular pathways suggests they could be effective in developing new HuR inhibitors, targeting a protein crucial for regulating cancer-related gene expression. Compounds C1-C20 were designed by using Discovery Studio (DS) software.

In this study, a systematic approach involves scaffold hopping followed by additional research such as molecular docking, ADMET, drug-likeness, toxicity prediction, molecular dynamic (MD) simulation, and binding free energy analysis was used to discover novel Human Antigen R (HuR) inhibitors.

In molecular docking, 1,4-Naphthoquinone derivatives showed better interactions with the HuR protein compared to that of the conventional HuR inhibitor MS-444. Among twenty 1,4-Naphthoquinone derivatives, most of the compounds showed favorable pharmacokinetic characteristics. In the toxicity prediction model, most of the designed compounds were neither mutagenic nor carcinogenic. According to MD simulation, C5 is more stable than MS-444.

The designed 1,4-Naphthoquinone derivatives have been found to be crucial structural motifs for the discovery of novel HuR inhibitors, which was well supported by the in-silico screening and molecular modeling methods.

The present study aims to identify the synthesis and structural characterization of acyl hydrazone-sulfonamide-containing compounds that were tested in vitro on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII.

Herein, acyl hydrazone derivatives containing the primary sulfonamide moiety were synthesized via a three-step synthetic pathway starting from the commercially available 4-sulfamoyl benzoic acid. Structural characterizations of the final compounds were assessed through IR IR, ¹H-NMR, ¹³C-NMR, and elemental analyses. The in vitro profiling activity of the final compounds on the Carbonic Anhydrases (CAs; EC 4.2.1.1) I, II, IX, and XII were performed by means of the stopped-flow technique and revealed nanomolar inhibitory potencies on the selected targets. Molecular docking and molecular dynamic simulations afforded a detailed understanding of the binding modes of the most effective compounds.

We reported the synthesis and structural characterization of 25 acyl hydrazone-sulfonamide-containing compounds that were tested in vitro on the hCAs I, II, IX, and XII isoforms for their inhibitory features. Overall, all compounds showed nanomolar inhibition potencies on the panel of hCAs considered, and their binding modes were deciphered by means of in-silico studies. Molecular docking followed by MD simulations confirmed the stability of 4l-hCA I, 4n-hCA II, 4t-hCA II, 4v-hCA XII, and 4w-hCA XII complexes.

This study presents a deep understanding of the structural determinants influencing the affinity and selectivity of the designed compounds towards different hCAs, thus offering valuable insights for further optimization and development in the field.

The occurrence of gain of function mutations in STAT5B has been associated to survival, and drug resistance in Leukemia. In silico screening of compounds having inhibitory potential towards mutated proteins, can be helpful in the development of specific inhibitors.

This study was designed to screen selected JAK-STAT mutations in leukemia patients and virtual exploration of molecular interaction of potential inhibitors with their mutated products.

In total 276 patients were randomly recruited for this study. Demographic and clinical data were summarized. The genetic status of JAK1^V623A, JAK2 ^S473 and STAT5B^N642H were screened through allele specific PCR. In-silico analysis was performed on wild type and mutant protein sequences retrieved from Protein databank. The ligands and protein were prepared through standard protocols, and docking was performed through Auto Dock Vina 1.2.0.

Acute lymphoblastic leukemia comprises 70% of the total patients. Male to female ratio was 3:1. All the patients were homozygous for JAK1^V623A, JAK2 ^S473 major allele. However, 6 patients (5 male, 1 female) with ALL were STAT5B^N642H+. The molecular docking of the ligands to wild type and STAT5B^N642H+revealed that AC-4-130, Pimozide, Indirubin and Stafib-2 have higher but differential docking affinities for SH2-domain of both normal and mutated STAT5B. However, AC-4-130 has a higher affinity for wild type and Stafib-2 has stable molecular interaction with STAT5B^N642H+.

The aggressive form of pediatric leukemia, carrying STAT5B^N642H+ mutation is identified in the studied population. It is predicted that AC-14-30 and stafib-2 have potential for inhibition of constitutively active STAT5B if optimized for use in combination therapy.

Cancer is a group of diseases caused by uncontrollable cell growth. Herbal medicines, derived from plants, have been used for centuries across cultures for their therapeutic benefits, effectively treating conditions like cancer. This study represents the anticancer effects of fractions of some medicinal plant extracts along with their apoptotic studies and their induction through p53-mediated Bax and Bcl-2 mRNA expression in HepG2 and U87MG cells.

The fractionation of crude methanolic extracts was done using Column Chromatography and Thin Layer Chromatography. The fractions were analysed for cytotoxicity against both the cell lines by MTT assay. Cancer cells were treated with 2 most active fractions and their mechanism of apoptosis induction was assessed by Flow Cytometry studies and the mRNA expression levels of p53, Bax, and Bcl-2 were determined by Reverse Transcriptase PCR. The presence of phytoconstituents in the active fractions was analysed by GC-MS.

The active fractions revealed the apoptosis induction in both the cell lines and the RT-PCR studies suggested the mechanism of apoptosis induction through upregulation of p53 and Bax and downregulation of Bcl-2 mRNA. The GC-MS analysis of active fractions from Balanites aegyptiaca and Pterocarpus marsupium revealed the presence of phytochemicals such as 4-O-Methylmannose, Oleic acid, Erucic acid, etc. which might have contributed to the anti-proliferative and apoptotic effects of these fractions.

4-O-Methylmannose was the major component identified with the highest peak area of 59%. The fractions from all the 4 plant extracts demonstrated significant cytotoxic effects on the liver (HepG2) and brain (U87MG) cancer cell lines, with particular emphasis on the active fractions BA FII, PM FII, and PM FIII. Additionally, the mechanisms of apoptosis induction through the modulation of p53, Bax, and Bcl-2 pathways, along with the presence of bioactive compounds further support the anticancer efficacy of these plant extracts. Also, to the best of our knowledge, this is the first study on fractions of Balanites aegyptiaca and Pterocarpus marsupium against U87MG cells.

The results highlight the promising potential of plant-derived natural products as anticancer agents. These findings provide valuable insight into the potential of herbal medicines and encourage further exploration of plant-based therapies for cancer treatment.

The toxic effects of cisplatin limit its therapeutic efficacy on hepatocellular carcinoma (HCC). Cisplatin(IV) (Pt(IV)) with better stability needs an effective drug delivery strategy. Here, we explored the toxic and inhibitory effects and cell Pt contents of monomethoxyl poly(ethylene glycol)-block-poly(e-caprolactone)-block-poly(L-lysine) (MPEG-b-PCL-b-PLL)/Pt(IV) micelles (M(P3)) on HCC, and evaluated the therapeutic effect of (M (Pt (IV)) on HCC in vitro and in vivo.

We successfully constructed HCC model in BALB/c mice and prepared M(P3). The H22 and HepG2 cells were incubated with cisplatin, M(P3), and cisPt(IV)-(COOH)2 at 2, 10, 20, 50, 100 and 250 µM equivalent platinum (Pt) concentrations for 48 h and at 5 µM for 2/6 h. The HCC mice received cisplatin, M(P3), and cisPt(IV)-(COOH)2 (5 mg equivalent Pt/kg, once a week) for five weeks. The cell activity was assessed by MTT assay. The Pt contents were assayed by an inductively coupled plasma mass spectrometer (ICP-MS). The liver tumor weight was measured. The levels of liver tumor hepatorenal function indicators and malignant indicators were estimated by biochemical analysis and Western blot.

The activity of H22 and HepG2 cells: cisPt(IV)-(COOH)2-treated > M(P3)-treated > cisplatin-treated. The Pt contents of H22 and HepG2 cells: M(P3)-treated > cisplatin-treated > cisPt(IV)-(COOH)2-treated cells. The hepatorenal function of HCC mice: M(P3)-treated > cisPt(IV)-(COOH)2-treated > cisplatin-treated. According to the weight and levels of malignant indicators of liver tumor, the therapeutic effect on HCC mice: cisplatin-treated > M(P3)-treated > cisPt(IV)-(COOH)2-treated.

Although the inhibitory effect of M(P3) on HCC is not as good as cisplatin, M(P3) has significantly lower hepatorenal toxicity and remarkably higher cell Pt contents.