AI-Driven Computational Design of Peptide-Based WWP1 Inhibitors as Promising Therapeutic Agents Against Breast Cancer, Including Triple-Negative Subtype
WI23-B is highlighted as a promising lead peptide with potent WWP1 inhibitory activity and synergistic antiproliferative effects when combined with PI3K inhibitors, and has the potential to reshape therapeutic strategies for BC and TNBC by enabling more effective and less toxic treatment regimens.
The combined computational and experimental approach enabled the identification of peptides with selective cytotoxic effects and favorable predicted immunogenic profiles, demonstrating that integrating computational screening with experimental validation is an effective strategy for accelerating the discovery of selective anticancer peptides.
Isabella Fagundes Gurgel, Ana Carolini Almeida Marcarini, Carlos Marchiorio Lacerda et al.· International Journal of Pep...· 0 citations
Triple-negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype characterized by a paucity of effective therapeutic options. Consequently, the development of targeted therapies constitutes a promising strategy for TNBC treatment. It has been demonstrated that combining CDK12 and PARP1 inhibitors can trigger synthetic lethality in TNBC cells. In the present study, employing a pharmacophore fusion strategy, we designed and synthesized a series of dual-target inhibitors against CDK12 and PARP1. Among them, compound 20b exerted potent inhibition activity against both CDK12 and PARP1 at nanomolar concentrations. It exhibited markedly superior antiproliferative effects compared with single-target inhibitors and effectively reduced pSer2-CTD (Ser2 phosphorylation) and PAR levels in TNBC cells. Furthermore, compound 20b produced robust colony formation inhibitory effects in TNBC cell lines, accompanied by cell cycle arrest and apoptosis induction. The dual-target CDK12/PARP1 inhibitor 20b developed herein represents a novel lead molecule for TNBC drug development.
Zhi-Jian Zhong, Miao Sun, Zhi-Wen Luo et al.· European journal of medicina...· 0 citations
The serine/threonine kinase PAK1 is increasingly recognized as a pivotal regulator of tumor progression and immune evasion in triple-negative breast cancer (TNBC). However, the development of PAK1 inhibitors with both high potency and favorable drug-like properties remains challenging. Herein, we report the design, synthesis, and biological evaluation of a series of novel PAK1 inhibitors guided by a conformation-driven optimization strategy. We identified ZMF-28, a potent PAK1 inhibitor with an IC50 of 0.02 μM, exhibiting high selectivity in the kinase profiling assay. Notably, ZMF-28 exhibited 10-fold higher cellular antiproliferative activity against 4T1 cells (IC50 = 0.22 μM) than the clinical candidate FRAX-486, and achieved significant tumor growth inhibition in vivo without overt toxicity, and demonstrated favorable pharmacokinetics. Mechanistically, ZMF-28 directly binds to PAK1 and blocks its kinase activity, thereby downregulating PD-L1 expression and reversing the immunosuppressive tumor microenvironment, representing a dual-action therapeutic strategy for TNBC. These findings establish ZMF-28 as a promising therapeutic candidate for TNBC and highlight the value of conformation-guided design in kinase inhibitor discovery.
Hong-Lei Bao, Yu-Pei Lai, Xi Zhao et al.· European journal of medicina...· 0 citations
Non-small-cell lung cancer (NSCLC) remains the leading cause of lung cancer–related mortality, largely driven by aberrant activation of the epidermal growth factor receptor (EGFR). Despite the clinical success of EGFR tyrosine kinase inhibitors (TKIs), intrinsic and acquired resistance, coupled with safety concerns, highlight the need for novel, safer inhibitors. Natural products represent an underexplored source of structurally diverse bioactive compounds with favorable biocompatibility. In this study, a comprehensive in silico approach is used to evaluate phytochemicals from Adenium obesum as potential candidate EGFR-targeting compound. Initially, sixteen phytochemicals were first assessed for predicted antineoplastic activity using PASS. High-scoring molecules were docked against the EGFR kinase domain (PDB ID: 1M17), besides performed detailed protein–ligand interaction analysis, drug-likeness and ADMET profiling, toxicity prediction and 100-ns molecular dynamics (MD) simulations. PASS-based bioactivity prediction revealed strong anticancer potential among the sixteen screened compounds, with consistently high antineoplastic and antiproliferative activity probabilities (Pa > 0.79) and low inactivity scores, supporting their selection for subsequent docking, ADMET, and molecular dynamics analyses. Next, several phytochemicals exhibited strong docking affinities, with Cardenolide achieving the highest binding score (–9.9 kcal/mol) and forming stable interactions with key catalytic residues. A 100-ns MD simulation confirmed the structural stability, persistent binding, and dynamic integrity of the EGFR–Cardenolide complex under physiological conditions. Importantly, interaction mapping revealed that Cardenolide engages conserved and functionally critical regions of the EGFR kinase domain associated with catalytic activity and structural stability, supporting its mechanistic relevance as an ATP-competitive scaffold. Additionally, predicted pharmacokinetic and toxicity profiles further supported Cardenolide’s suitability as a drug-like candidate. Collectively, these results identify Cardenolide as a computationally prioritized candidate with favorable predicted EGFR-binding characteristics, structural stability, and physicochemical and toxicity profiles. However, as the present study is based entirely on computational analyses, these findings should be considered hypothesis-generating and do not establish EGFR inhibitory activity or therapeutic efficacy. Experimental validation, including biochemical kinase inhibition and cellular assays, is therefore required to determine the actual EGFR inhibitory potential and anticancer activity of Cardenolide. Nevertheless, the findings provide a rational basis for prioritizing Cardenolide for further experimental investigation and illustrate the potential of Adenium obesum phytochemicals as a source of candidate EGFR-targeting compounds for future NSCLC drug discovery.
Md. Naziur Rahman, Abu Yousuf Hossin, S. Talukder et al.· PLoS ONE· 0 citations
Pancreatic cancer remains one of the most lethal malignancies because of late diagnosis, aggressive progression, therapy resistance, and limited effective treatment options. Bromodomain-containing protein 4 (BRD4) is an important epigenetic regulator implicated in pancreatic cancer progression through its role in transcriptional control, cell proliferation, and survival signaling. Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a potential strategy for eliminating disease-associated proteins through ubiquitin-proteasome-mediated degradation rather than transient pharmacological inhibition. In this study, an AI-assisted and structure-guided computational workflow was used to design and virtually prioritize BRD4-targeting PROTAC candidates recruiting DCAF15 as the E3 ligase component. The workflow integrated protein-structure evaluation, pharmacophore-based ligand screening, ADMET and Lipinski filtering, binary protein-ligand docking, molecular-interaction analysis, rational linker selection, BRD4-DCAF15 protein-protein docking, PROTAC-mediated ternary-complex docking, and molecular dynamics simulation. The results identified CLTTMPBA-linker-E7820 as a computationally prioritized PROTAC architecture with favorable predicted binding behavior, residue-level interaction patterns, and simulated ternary-complex stability. Importantly, this study is entirely computational and should be interpreted as an early-stage in silico prioritization framework rather than experimental evidence of BRD4 degradation or anticancer efficacy. The proposed BRD4-DCAF15 PROTAC candidates represent lead hypotheses that require biochemical, cellular, pharmacological, and in vivo validation, including confirmation of target engagement, ternary-complex formation, proteasome-dependent BRD4 degradation, downstream transcriptional modulation, pancreatic cancer cell inhibition, selectivity, pharmacokinetics, toxicity, and antitumor efficacy.
Bing-Yan Du, Kun-Jie Wang, Zhu Wu et al.· American Journal of Cancer R...· 0 citations
Globally, Triple-Negative Breast Cancer (TNBC) has huge unmet medical need as it has limited targeted therapeutic options. However, it has well-known therapeutic vulnerabilities for selective inhibition of pathways like EGFR, m-TOR, PARP, EZH2, PD1-PDL1 etc. Analysis of publicly available databases clearly suggest that the concomitant EZH2 and EGFR overexpression results in poor survival of TNBC patients compared to their individual overexpression, underscoring the strong rationale for dual-targeted therapeutic intervention. Herein, potent, tumor cell selective chemical probes were designed and synthesized that simultaneously binds to both EZH2 and EGFR and inhibit their pro-tumorigenic functions in TNBC. SAR driven optimized lead molecule S-023-0996 (41a) proficiently binds and inhibits dual targets dampening tumor cell proliferation, migration and invasion in vitro with superior efficacy and safety than individual drug combinations (EZH2 inhibitor, Tazemetostat and EGFR inhibitor, Gefitinib). Mass spectrometry-based proteomic profiling revealed translation inhibition is a key differentiating factor for achieving robust anti-tumor effects of S-023-0996. S-023-0996 has favourable pharmacokinetic properties and inhibits tumor growth and metastasis in vivo more efficiently than comparator drug combinations in preclinical TNBC models. Our results represent the discovery of first-in-class dual EZH2-EGFR inhibitor and establish the possibility of targeting two vulnerabilities of TNBC together with a single chemical entity.
