Gabriele Carullo

Acute myeloid leukemia (AML) is the most common form of acute leukemia. It is characterized by unfavorable prognosis, elevated rates of recurrence, short overall survival and high mortality rates. Genetic and epigenetic aberrations contribute to its initiation and progression, presenting a considerable clinical challenge. Genomic investigations revealed that FMS‐like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase regulating the proliferation and differentiation of hematopoietic cells, is overexpressed in AML leukemic blasts. To date, FDA has approved only three FLT3 inhibitors for targeted AML therapy (midostaurin, gilteritinib, quizartinib). These molecules feature several nitrogen atoms; in particular quizartinib contains an oxazole and a urea group that are involved in interactions with FLT3 kinase domain. Similarly, different N‐containing heterocycles have proven to play a key role in other FLT3 inhibitors. Though small‐molecule FLT3 inhibitors encompass various chemical classes, N‐containing heterocycles and particularly the azole core represent the most common scaffold. The electron‐rich properties of the azoles allow them to easily bind with enzymes and receptors. Based on this, we will provide a general overview of FLT3 inhibitor classes in AML, along with a comprehensive report on azole‐based structures, reviewing recent contributions to the field.

Chronic lymphocytic leukemia (CLL) is a hematological malignancy characterized by the accumulation of mature CD5⁺ B cells largely due to defective apoptosis. Prolonged leukemic cell survival has been linked to downregulation of the pro-apoptotic adaptor p66Shc and its transcription factor STAT4, both of which are typically reduced in CLL patients. To date, a clear mechanistic explanation for STAT4 deficiency in CLL has not yet been provided. Restoring STAT4 expression or activating its residual function may represent an attractive therapeutic strategy. Histone deacetylase 6 (HDAC6) directly deacetylates and suppresses STAT4 in T lymphocytes, suggesting that a similar mechanism may operate in CLL cells. In this study, we hypothesized that HDAC6-mediated STAT4 inhibition also occurs in CLL cells and contributes to leukemic cell survival. Accordingly, we tested the potent HDAC6 inhibitor Taginostat (HDAC6 IC₅₀ = 7.9 nM) and found that it enhanced p66Shc expression and restored apoptosis in CLL cells. These effects were reproduced by HDAC6 silencing. Flow cytometric and western blot analyses showed that Taginostat boosted residual STAT4 activity by enhancing its phosphorylation. Moreover, transient transfection with STAT4-luciferase or STAT4-green fluorescent protein (GFP) constructs demonstrated that Taginostat promoted both the nuclear translocation and transcriptional activity of STAT4. In addition, in vivo experiments conducted in the Eµ-TCL1 mouse model of CLL demonstrated that Taginostat treatment counteracted disease development, significantly reducing the leukemia burden. Collectively, these findings validate HDAC6 inhibition as a valuable therapeutic strategy for promoting STAT4 activation in CLL cells, restoring the apoptotic cascade, and counteracting disease progression.

Lysine-specific demethylase 4 A (KDM4A) is an Fe²⁺-dependent epigenetic regulator implicated in various cancers, representing an emerging target for anticancer drug development. However, the high polarity of its catalytic pocket poses a significant challenge in designing potent small-molecule inhibitors. In this study, a structure-based virtual screening workflow was implemented to optimize the known KDM4A inhibitor QC6352 and design novel isonicotinic acid derivatives with improved predicted binding affinity and dynamic stability. Two Python-based workflows employing fragment replacement and molecular breeding strategies were developed to generate virtual libraries while retaining the isonicotinic acid core. A total of 135,000 derivatives were produced and subjected to a hierarchical screening protocol involving molecular docking, ADMET-based filtering, induced fit docking (IFD), molecular dynamics (MD) simulations, and MM-GBSA rescoring. ADMET filtering was based on standard QikProp drug-likeness and pharmacokinetic criteria to prioritize compounds with acceptable predicted physicochemical, absorption, distribution, and safety-related profiles. Among the screened derivatives, QC-L1A and QC-L2B showed the most favorable overall profiles compared with the reference compound QC6352 across multiple computational parameters. QC-L1A exhibited the most favorable binding free energy (ΔG_bind = − 30.96 kcal/mol), representing a 3.12 kcal/mol improvement over QC6352 (− 27.84 kcal/mol), along with the lowest mean RMSD (0.807 Å), indicating marked conformational stability. QC-L2B achieved the most favorable IFD score (− 751.02 kcal/mol), surpassing QC6352 by 7.64 kcal/mol, and yielded a ΔG_bind of − 29.62 kcal/mol. MD simulations revealed stable coordination between the conserved isonicotinic acid core and the catalytic Fe²⁺ ion, together with persistent interactions with key active-site residues. Selectivity analysis, performed by IFD-based profiling against KDM4 isoforms and other related JmjC demethylases, indicated a preferential binding profile toward KDM4 family members, particularly KDM4A and KDM4D. Retrosynthetic feasibility was assessed using the Spaya CASP platform, with both lead compounds showing favorable RScore values and practical synthetic routes. Accordingly, these findings highlight the effectiveness of a fragment-guided computational workflow for rational inhibitor optimization and introduce promising scaffolds for KDM4A-targeted drug design.

ESKAPE bacteria represent a global threat to public health. These microorganisms employ a type of cell–cell communicationnamed “quorum sensing (QS) system,” which involves the activation of specific signals to modulate drug resistance and pathogenic behaviors. Noteworthy, resistance of Pseudomonas aeruginosa to antibiotics is increasing, thus leading to a greater interest in the development of new antibacterial compounds by exploring valuable targets such as its complex QS system. This review intends to provide an extensive report about the advances in the identification of promising P. aeruginosa QS inhibitors as potential novel therapeutic options. This work represents a comprehensive analysis of research articles available on Pubmed, Scopus, and Google Scholar, from January 2020 to July 2025, referring to promising antivirulence compounds, affecting P. aeruginosa QS system.

Infectious diseases remain a major global health challenge, accounting for millions of deaths annually and placing an increasing burden on healthcare systems worldwide. The rapid emergence of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) bacterial strains, together with recurrent outbreaks of viral infections such as SARS‐CoV‐2, Ebola, Zika, Monkeypox, and influenza, underscores the urgent need for novel therapeutic agents with diverse mechanisms of action. In this context, indolizines, isoindoles, and isoindolinones represent promising scaffolds in anti‐infective drug discovery due to their unique structural features, versatile reactivity, and ability to engage multiple biological targets. This review provides an updated overview of the medicinal chemistry of indolizine and isoindoles, with particular emphasis on compounds demonstrating activities against infectious pathogens. Representative examples are highlighted to illustrate structure–activity relationships (SARs), scaffold‐based optimization strategies, and emerging mechanistic insights. Relevant synthetic methodologies are discussed only in the context of biologically active compounds to provide a framework for rational design. Collectively, this review underscores the therapeutic potential of indolizine‐ and isoindole‐derived scaffolds as versatile frameworks for anti‐infective drug development and highlights opportunities for further chemical and biological exploration.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen for which new antimicrobial strategies are urgently needed. To facilitate the establishment of the infection, P. aeruginosa produces a remarkable assortment of both cell-associated and extracellular virulence factors. The expression of numerous virulence traits is regulated by the pqs quorum sensing (QS) system, which relies on multiple enzymes for the biosynthesis of 2-alkyl-4-quinolone (AQ) signal molecules and on the transcriptional regulator PqsR, whose activity is triggered by AQ binding. Herein, we report on the design and synthesis of novel quinazolinone-based PqsR modulators, which led to the identification of two novel compounds endowed with anti-PqsR activity in the submicromolar range. Additionally, these derivatives inhibited the production of PqsR-controlled virulence factors in laboratory strains and clinical isolates of P. aeruginosa.