Biology subjects

Benedetti, R.

Publications and source records attributed to Benedetti, R..

3 recordsLinked to original sources

bioRxiv2026

Targeting the Tumor-Stroma Crosstalk: An AI-Based Virtual Screening Strategy for Dual MET/SMO Inhibitors in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense desmoplastic tumor microenvironment (TME) that limits drug penetration and promotes immune evasion. Effective treatment, therefore, requires simultaneous modulation of multiple signaling pathways. Here, we describe a directed polypharmacological strategy to identify dual modulators of c-MET and Smoothened (SMO), aiming to disrupt the protective stroma through SMO inhibition while directly suppressing tumor cell survival via c-MET targeting. An AI-guided virtual screening workflow combining the machine-learning platform PyRMD, trained on known c-MET and SMO ligands, with structure-based molecular docking was applied to a library of over 9 million compounds. This approach led to the identification of compound 21, an aminopyrimidine-benzamide-phenoxyquinoline derivative, as a dual c-MET/SMO inhibitor. Biochemical and cellular studies demonstrated that compound 21 selectively binds the SMO orthosteric site (pKi = 5.60), inhibits agonist-induced GLI (Glioma-associated oncogene) signaling (pIC50 = 5.50), and potently suppresses c-MET kinase activity (pIC50 = 6.94). Western blot analyses further revealed that compound 21 promotes ubiquitin-proteasome-mediated degradation of c-MET, eliminating receptor availability and limiting compensatory resistance signaling. In 3D heterotypic models comprising MIAPaCa2 pancreatic cancer cells and CAF154-hTERT fibroblasts, dual inhibition of SMO-mediated stromal support and c-MET-driven tumor progression resulted in greater cytotoxicity than the combination of the selective inhibitors Sonidegib and PHA-665752. Overall, compound 21 overcomes stromal-mediated resistance, enhances tumor cell death, and validates dual SMO/c-MET targeting as a promising single-agent therapeutic strategy for PDAC. One Sentence SummaryAn AI-identified dual SMO/c-MET inhibitor overcomes stromal resistance and degrades c-MET to suppress pancreatic cancer.

cancer biology↗

bioRxiv2023

Irreversible inhibition of TRF2TRFH recruiting functions: a strategy to induce telomeric replication stress in cancer cells.

The shelterin component telomeric repeat-binding factor 2 (TRF2) is an essential regulator of telomere homeostasis and genomic stability. Mutations in the TRF2TRFH domain physically impair t-loop formation and prevent the recruitment of several factors that promote efficient telomere replication, resulting in a telomeric DNA damage response. Here, we design, synthesize, and biologically test covalent cyclic peptides that irreversibly target the TRF2TRFH domain. We identify APOD53 as our most promising compound. APOD53 forms a covalent adduct with a reactive cysteine residue present in the TRF2TRFH domain and induces phenotypes consistent with TRF2TRFH domain mutants. These include induction of a telomeric DNA damage response in the absence of fusions, increased telomeric replication stress, and impaired recruitment of regulator of telomere elongation helicase 1 (RTEL1) and structure-specific endonuclease subunit (SLX4) to telomeres. We demonstrate that APOD53 impairs cell growth in both a telomerase-positive and an ALT cell line, while sparing the viability of non-cancerous cells. Finally, we find that co-treatment with APOD53 and the G4 stabilizer RHPS4 further exacerbates telomere replication stress.

cancer biology↗

bioRxiv2021

DNA Mutations via Chern-Simons Current

We test the validity of a possible schematization of DNA structure and dynamics based on the Chern-Simons theory, that is a topological field theory mostly considered in the context of effective gravity theories. By means of the expectation value of the Wilson Loop, derived from this analogue gravity approach, we find the point-like curvature of genomic strings in KRAS human gene and COVID-19 sequences, correlating this curvature with the genetic mutations. The point-like curvature profile, obtained by means of the Chern-Simons currents, can be used to infer the position of the given mutations within the genetic string. Generally, mutations take place in the highest Chern-Simons current gradient locations and subsequent mutated sequences appear to have a smoother curvature than the initial ones, in agreement with a free energy minimization argument.

biophysics↗