Aug 2026· Science Advances· Vol 12· 0 citations· 46 references
Medicine
TL;DR
CS18 is established as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.
Abstract
Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship–driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, restores E2F1-mediated apoptosis, and induces mitotic catastrophe. It exhibits broad-spectrum anticancer activity and synergizes with poly(ADP-ribose) polymerase (PARP) inhibitors in multiple cancer types and enhances osimertinib sensitivity in EGFR-mutated non–small cell lung cancer (NSCLC) cells. CS18 demonstrates efficacy in patient-derived breast cancer xenografts and overcomes osimertinib resistance in refractory NSCLC in vivo. These findings establish CS18 as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.
Exportin 1 (XPO1/CRM1) is a clinically validated anticancer target whose inhibition blocks nuclear export and promotes cancer cell apoptosis. Current XPO1 inhibitors rely on covalent Michael addition to Cys528 in the nuclear export signal binding groove of XPO1. Here, we describe a novel XPO1 inhibitor, FR-027, that targets Cys528 through nucleophilic aromatic substitution. In contrast to clinical-stage XPO1 inhibitors selinexor and eltanexor, FR-027 acts reversibly and does not promote XPO1 protein degradation. Structural analysis of the XPO1-FR-027 complex reveals covalent modification of Cys528 and a closed-groove conformation that prevents degradation. FR-027 demonstrates potent on-target activity across multiple cancer cell types and delays disease progression while extending overall survival in xenograft and syngeneic models, including intracranial tumors. Notably, FR-027 does not induce significant thrombocytopenia, lymphopenia, or neutropenia in heavily treated mice. These findings underscore the distinct molecular and pharmacological properties of FR-027 and support its further evaluation for clinical development in diseases with significant unmet medical needs. XPO1 is a clinically validated anticancer target but inhibition with covalent drugs, such as selinexor, can cause significant toxicities. Here, the authors design and characterise FR-027, a reversible covalent inhibitor of XPO1 that does not induce XPO1 degradation, demonstrating strong antitumour activity, including in brain tumours, with an improved safety profile in mice.
Janne Van Hauwenhuyse, F. Reniers, L. Persoons et al.· Nature Communications· 0 citations
A dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction between UBE2M and DCN1, which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs) and histone deacetylase (HDAC) activity is developed.
Tao Zheng, Yigui Li, Yunyuan Huang et al.· Journal of Medicinal Chemist...· 0 citations
Platinum-based chemotherapy remains one of the standard treatments for advanced non-small cell lung cancer (NSCLC); however, most patients eventually relapse because of acquired resistance. A major driver of therapeutic resistance is hyperactivation of the DNA damage response (DDR), which allows tumor cells to repair chemotherapy-induced DNA lesions and evade cytotoxic stress. The deubiquitinating enzyme USP10 stabilizes multiple DDR and pro-survival proteins, making it an attractive therapeutic target for re-sensitizing resistant tumors. Inhibition of USP10 may impair DNA repair signaling and enhance anti-tumor activity in resistant NSCLC models. We developed selective and potent USP10 inhibitors through medicinal chemistry optimization. GL-458 was identified as the lead USP10 inhibitor and demonstrated improved selectivity in deubiquitinase (DUB) assays compared with previously reported USP10 inhibitors, including Wu-5 and P22077. P22077 functions as a covalent, non-specific inhibitor, whereas Wu-5 is a non-covalent, non-selective inhibitor. In cellular viability MTT assays, GL-458 demonstrated greater potency, with approximately 3-fold lower IC50 values than Wu-5 and approximately 1.7-fold lower IC50 values than P22077. GL-458 target selectivity and target-dependent cytotoxicity were further evaluated using mouse KRAS/TP53-driven (KP) and USP10-knockout KPU NSCLC models. MTT and colony formation assays demonstrated robust, dose-dependent suppression of proliferation and clonogenic survival. Combination treatment studies using CellTiter-Glo showed that GL-458 effectively re-sensitized cisplatin-resistant cells. Flow cytometric analysis using the Click-iT EdU assay demonstrated early G0/G1 cell-cycle arrest accompanied by ATM/ATR activation, increased gamma-H2AX, and elevated cleaved PARP-1 expression. Immunofluorescence analyses revealed accumulation of gamma-H2AX, 53BP1, and Chk1 foci, consistent with impaired DNA repair capacity. Co-treatment with ATM inhibitors further validated the involvement of DDR signaling in mediating the anti-tumor effects of USP10 inhibition. Generative AI tools were used solely for language editing and improvement of abstract clarity; all scientific content, data interpretation, and conclusions were generated and verified by the authors.
Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh, Babita Kushwaha. Dorandish, Yubin Ge, Navnath S Gavande. Selective USP10 inhibition by GL-458 re-sensitizes platinum-resistant non-small cell lung cancer through DNA damage response disruption [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A062.
Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh et al.· Clinical Cancer Research· 0 citations
Poly(ADP-ribose) polymerase inhibitors (PARPi) are a first-line treatment for epithelial ovarian cancer (EOC) patients, but the development of resistance limits long-term therapeutic efficacy. Tumor acidosis is a hallmark of the tumor microenvironment that has been shown to promote resistance to cancer therapies, suggesting that it may impact PARPi response. Here, we demonstrated that the acidic tumor microenvironment drives a p300-dependent mechanism of PARPi resistance in EOC. Pathologically acidic pH enhanced DNA damage repair, reduced PARPi-induced PARP1 trapping, and attenuated the anti-tumor efficacy of PARPi. A CRISPR-Cas9 screen identified p300 as a druggable mediator of acidosis-induced PARPi resistance. Mechanistically, acidic pH activated an ERK-p300-PARP1 signaling axis that acetylated PARP1 at lysine 505 (PARP1 K505Ac), thereby alleviating PARPi-mediated PARP1 trapping and DNA damage. Elevated PARP1 K505Ac was associated with clinical resistance to PARPi and poor overall survival. In patient-derived and syngeneic EOC models, pharmacologic inhibition of p300 synergized with PARPi to suppress tumor growth. Together, these findings identify p300 as a key mediator of acidosis-induced PARPi resistance and a promising therapeutic target to enhance PARPi efficacy.
Kaixin Cheng, Hao Nie, Wei Zhou et al.· Cancer Research· 0 citations
DNA topoisomerase IIα (Topo IIα) is essential for maintaining genomic stability during DNA replication and mitosis and is highly expressed in cancer cells, making it a promising target for anticancer therapy. In this study, bis-thiourea derivatives were investigated for their Topo IIα inhibitory activity and anticancer potential using in silico and in vitro studies. Molecular modeling demonstrated that compound 8 exhibited favorable binding affinity and stability within the ATPase domain of Topo IIα. Biochemical assays revealed that compound 8 inhibited Topo IIα activity and showed potent cytotoxicity against several cancer cell lines, particularly A549 cells. Mechanistic studies showed that compound 8 inhibited A549 cell migration and invasion by upregulating E-cadherin while downregulating the mesenchymal markers N-cadherin and vimentin, as well as the EMT-associated transcription factor Slug. Furthermore, compound 8 induced G1-phase arrest by downregulating cyclins D1 and E2 while upregulating p21. These results suggest that compound 8 represents a promising lead for Topo IIα-targeted cancer therapy.
Poly(ADP-ribose) polymerase (PARP) inhibitors are highly effective in BRCA-deficient tumors, yet their therapeutic benefit in BRCA-proficient cancers remains limited. Here, we demonstrate that YCH1899, a next-generation, resistance-overcoming PARP inhibitor, elicits significantly stronger type I interferon signaling than currently approved PARP inhibitors in BRCA-proficient tumor cells. Mechanistically, YCH1899 facilitates the accumulation of cytosolic DNA, thereby robustly activating the cGAS–STING–IRF3 pathway. Consequently, YCH1899 exhibits potent inhibitory effects on the growth of various BRCA-proficient tumors in a STING-dependent manner and enhances the infiltration of CD8⁺ T cells within the tumor microenvironment. To identify tumor-intrinsic regulators of this immune response, we conducted in vivo CRISPR screens, which revealed USP20 as a prominent regulator. The genetic ablation of USP20 markedly diminished the antitumor immunity induced by YCH1899 in vivo, suggesting that USP20 may serve as a potential predictive biomarker. Furthermore, combining YCH1899 with STING agonists synergistically amplifies interferon pathway activation, driven by enhanced phosphorylation of IRF3 at Ser173, resulting in superior tumor control and profound immune cell infiltration and activation within the tumor microenvironment. Collectively, our findings establish YCH1899 as a potent PARP inhibitor capable of extending clinical benefit to BRCA-proficient cancers and provide a rationale for its clinical combination with STING agonists to elicit robust antitumor immunity, even in patients resistant to PARP inhibitors.
Li Jia, Ming-Hao Cao, Yuting Sun et al.· Molecular Biomedicine· 0 citations
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