Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Online First
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Recent Advances in Therapeutic Potential of Dual-Acting Aromatase/COX-2
Available online: 26 March 2025More LessAromatase, a crucial enzyme assigned for transforming androgen into estrogen, has a vital function in the advancement of drug-resistant breast cancers that respond to endocrine treatments. Aromatase (CYP19A1) is a monooxygenase from the cytochrome P450 family that is involved in the conversion of androgens to estrogens. Breast cancer cells express aromatase activity, indicating that the tumor cells may be able to produce local estrogen. By inhibiting aromatase, serum estrogen levels decrease, which, in turn, hinders estrogen-driven cancer cell growth in hormone receptor-positive breast cancer cases. In this sense, the introduction of novel aromatase inhibitors could be a significant step forward in the fight against cancer. This is especially true in hormone-dependent cancers. Many compounds have been introduced as aromatase inhibitors, classified as steroidal or nonsteroidal. However, it should be noted that these drugs have encountered resistance in numerous cases, particularly in recent years. Thus, the search for new aromatase inhibitor drugs has always been critical. Newly, there seems to be a surge of enthusiasm in the discovery and production of molecules with dual inhibitory effects, which can inhibit two or more enzymes simultaneously. This method enables a significant reduction in potential drug resistance. The design of these compounds has an opportunity to significantly boost the efficacy of anti-cancer treatments by causing synergistic effects. This article offers a review of newly developed aromatase inhibitors with potential anticancer effects.
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Unraveling the Role of Tumor-infiltrating Immune Cells in Modulating Cancer Drug Resistance
Available online: 24 March 2025More LessTumor-infiltrating immune cells (TIICs) have been identified as critical components in the development of cancer drug resistance. This review aims to discuss the various types of TIICs, such as macrophages and T cells, that have been linked to cancer drug resistance. Furthermore, we explore the mechanisms by which TIICs contribute to drug resistance and how these mechanisms may differ across various tumor types. Additionally, we examine the potential of immune checkpoint inhibitors in combination with traditional cancer therapies as a strategy to overcome TIIC-mediated cancer drug resistance. In conclusion, this review provides an in-depth analysis of the current knowledge on the role of TIICs in cancer drug resistance and highlights potential avenues for future research to develop more effective treatment strategies. The findings presented in this review emphasize the importance of understanding the complex interactions between cancer cells and the immune system in order to develop novel therapeutic approaches that can overcome TIIC-mediated cancer drug resistance.
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Synthesis and Evaluation of Optical Properties, SHP2 Inhibitory Activity, and Cellular Imaging for Novel 2-Quinolone Derivatives
Authors: Chun Zhang, Yuting Yang, Li-Xin Gao, Suya Gan, Jia Li, Xin Wang, Yu-Bo Zhou and Wen-Long WangAvailable online: 17 March 2025More LessIntroductionAlthough the development of SHP2 inhibitors has made striking progress, there is no inhibitor in clinical evaluation because of the potential side effects induced by poor drug distribution. Fluorescence imaging technology is widely used in the process of diagnosis and treatment of diseases because of the advantages of rapid imaging and non-destructive detection and might provide a new way to explore the mechanism of drug-target interactions in intact tissue.
MethodsA series of 2-quinolone derivatives as fluorescent inhibitors against SHP2 were designed and synthesized, and their spectral properties and biological activities were evaluated in this report. The representative compound 8A had excellent fluorescence properties (: 562 nm, Stokes shift: 170 nm, fluorescence quantum yield: 0.072) and optical stability.
ResultsMoreover, compound 8A emitted a blue signal in SHP2WT U2OS cells and inhibited the SHP2 enzyme abilities (IC50: 20.16 ± 0.95 μM) without the extra combination of suitable fluorophores, linker, or selective-activated molecules.
ConclusionTherefore, we hope that compound 8A could act as a lead to develop novel, convenient, and bifunctional chemical tools to explore the mechanism of drug-target interactions in intact tissue and promote the integrated research progress of diagnosis and treatment of SHP2 related diseases.
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Recurrent Missense Driver STAT5B N642H Mutation in Children Transiting into Adolescence, with Acute Lymphoid Leukemia and its In silico Inhibition
Authors: Rehana Yasmin, Rashda Abbasi, Tajdar Jahangir Gohar, Hina, Nafees Ahmad and Sajid MalikAvailable online: 10 February 2025More LessBackgroundThe 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.
ObjectiveThis 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.
MethodsIn total 276 patients were randomly recruited for this study. Demographic and clinical data were summarized. The genetic status of JAK1V623A, JAK2 S473 and STAT5BN642H 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.
ResultsAcute lymphoblastic leukemia comprises 70% of the total patients. Male to female ratio was 3:1. All the patients were homozygous for JAK1V623A, JAK2 S473 major allele. However, 6 patients (5 male, 1 female) with ALL were STAT5BN642H+. The molecular docking of the ligands to wild type and STAT5BN642H+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 STAT5BN642H+.
ConclusionThe aggressive form of pediatric leukemia, carrying STAT5BN642H+ 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.
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A Systematic Quantitative Approach to Rational Drug Design and the Discovery of Novel Human Antigen R (HuR) Inhibitors
Authors: Juhi Dey, Kumari Kaushiki, KM Abha Mishra, Paga Sudheer and Kalyan Kumar SethiAvailable online: 04 February 2025More LessBackground1,4-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.
MethodsIn 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.
ResultsIn 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.
ConclusionThe 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.
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The Function of Poly (U) Binding Splicing Factor 60 (PUF60) in Disease Regulation
Authors: Huijuan Chen, Tian Guan, Jingfeng Song and Yihua ChenAvailable online: 03 January 2025More LessThe alternative splicing (AS) of pre-mRNA is an important process in controlling the expression of human genes, which can enrich the diversity of the proteome and regulate gene function. On the contrary, aberrant splicing contributes significantly to numerous human diseases progression, including tumors, neurological diseases, metabolic diseases, infections, and immune diseases. The PUF60, a protein related to RNA splicing, plays critical functions in RNA splicing and gene transcription regulation. In addition, it can achieve synergistic binding with U2AF65 on RNA through interactions in the pyrimidine region, promoting the splicing of introns with weak 3'- splice sites and pyrimidine bundles. Nevertheless, an increasing amount of evidence supports that it shows a significant overexpression pattern in the vast majority of cancer cells and is crucial for embryonic development, indicating that PUF60 may hold the post of a potential therapeutic target for such diseases. These studies have significantly increased our interest in PUF60. Thus, we briefly reviewed the structural domain characteristics of the PUF60, splicing mutants of PUF60, and the roles and functions in human diseases, including various cancers, infections of bacterium and viruses, myositis, and Verheij syndrome. Furthermore, the targeted PUF60 inhibitors and boundedness of the current research were elaborated on in the article. The article effectively communicates critical perception and insight, making it a precious resource for those interested in PUF60 research and treatment.
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