These studies establish selective inhibition of the PLK1 Polo-box domain as a viable therapeutic strategy, provide in vivo proof-of-concept for the REPLACE approach, and identify abbapolins as promising leads for advanced prostate cancer.
A substantial body of research implicates PRMTs in the pathogenesis of human diseases, primarily as oncoproteins or tumor suppressors in cancer. Starting from structure-based in silico screening of small-molecule databases, we predicted, synthesized, and assayed compounds aimed at specifically inhibiting selected PRMT family members. Unexpectedly, among several PRMT-inhibitory molecules we identified TR-07, a compound that selectively enhances the catalytic activity of PRMT1 in vitro. SAR analyses led to the design and synthesis of derivatives with increased potency in activating PRMT1 compared to TR-07 but at the cost of selectivity. TR-07 and its derivatives bind to the αY helix near the catalytic core of PRMT1. Treatment of pancreatic tumor cells with these PRMT1 activators enhanced global ADMA levels and augmented PRMT1’s apoptotic function in cell culture and mouse models. Our results establish TR-07 as the first selective, cell-active PRMT1 activator and underscore the therapeutic promise of this novel class of modulators.
Sepideh Salehipour-Bavarsad, Christian Iking, Jonas Kammertöns et al.· Journal of Medicinal Chemist...· 0 citations
Beyond enabling the discovery of several new potent and selective small molecules, these studies have allowed us to elucidate key parameters for potency, selectivity, and metabolic stability that should aid future efforts in RBP drug discovery.
G. M. Scherer, Jacob P. Sorrentino, A. K. Jaiswal et al.· Journal of Medicinal Chemist...· 0 citations
Targeted therapies have substantially advanced cancer treatment; however, therapeutic resistance remains a major challenge, particularly in lung cancer. Polo-like kinase 1 (PLK-1), a key regulator of mitosis, is frequently overexpressed in lung tumors and has emerged as an attractive anticancer target. Although PLK-1 inhibition induces robust antitumor effects in preclinical models, its translation into clinical benefit has been limited, particularly when used as monotherapy. Previous in vitro work from our group demonstrated that combining PLK-1 inhibition with the pro-apoptotic agent Navitoclax markedly enhanced cancer cell death by reducing mitotic slippage and promoting post-mitotic apoptosis. Here, we investigated whether this combinatorial strategy translates into therapeutic benefit in vivo. Using Lewis lung carcinoma (LLC1) cells, we evaluated the effects of BI2536 (a PLK-1 inhibitor) and Navitoclax, alone or in combination, in vitro and in male C57BL/6J mice using three lung cancer models: subcutaneous, intranasal, and intrapulmonary. The in vitro results corroborated the findings of our previous work, demonstrating synergistic effects. In the murine models, tumor progression, body weight, survival, and histopathological features were assessed to evaluate therapeutic efficacy and systemic toxicity. In the subcutaneous model, BI2536 monotherapy significantly reduced tumor volume compared with vehicle-treated controls, while Navitoclax alone and the combination therapy also produced tumor growth inhibition. In contrast, in the intranasal model, no significant differences were observed in body weight or survival among groups. Nonetheless, treatment with BI2536 alone or in combination with Navitoclax significantly reduced tumor cell proliferative activity. In the aggressive intrapulmonary (orthotopic) model, rapid disease progression and high mortality were observed across all groups. Notably, BI2536 treatment was associated with improved survival compared with Navitoclax monotherapy, whereas the combination therapy did not confer additional survival benefit. Histological analyses revealed highly proliferative tumors with pronounced cellular and nuclear atypia. Moreover, the BI2536 monotherapy group exhibited significantly greater necrosis/apoptosis than the other treatment groups, while diffuse and focal hepatic steatosis was observed exclusively in the combination group. Together, these findings indicate that while PLK-1 inhibition exerts antitumor effects in certain in vivo contexts, the therapeutic synergy observed in vitro with Navitoclax does not consistently translate to in vivo lung cancer models. This study highlights the challenges of translating combinatorial mitotic and apoptotic targeting strategies into effective in vivo therapies and underscores the importance of model selection and tumor microenvironment in preclinical drug evaluation.
Bárbara Pinto, Mateus Prates-Rodrigues, D. A. B. Nobre et al.· International Journal of Mol...· 0 citations
Background/Objectives: Pituitary neuroendocrine tumors (PitNETs) frequently exhibit invasive behaviors that complicate clinical treatment. While cyclin-dependent kinase 5 (CDK5) and lymphokine-activated killer T-cell-originated protein kinase (PBK, also known as PDZ-binding kinase) are implicated in tumor progression, their reciprocal regulatory mechanism remains unclear. This study aims to elucidate the CDK5-PBK interaction in PitNETs and identify potential therapeutic agents targeting this pathway. Methods: We utilized proximity labeling and phospho-specific assays to characterize the CDK5 and PBK interaction in PitNET cell lines. Immunohistochemical analysis was performed on patient tumor tissues to evaluate clinical relevance. Artificial intelligence (AI)-based virtual screening was employed to discover dual-target inhibitors. The therapeutic efficacy of the identified compound, proguanil hydrochloride, was subsequently evaluated using in vitro functional assays, alongside in vivo xenograft animal models. Results: We identified a mutual phosphorylation loop between CDK5 (at S159) and PBK (at T9) that activates insulin signaling, thereby promoting cellular proliferation and invasion in PitNETs. Patient tumor analysis revealed that the co-expression of phosphorylated CDK5 (S159) and PBK (T9) significantly correlates with tumor invasiveness (p < 0.001). Through AI screening, proguanil hydrochloride was identified as a candidate dual-target inhibitor. In vitro assays confirmed that it effectively reduces tumor cell growth, while in vivo xenograft studies validated its capacity to inhibit tumor progression. Conclusions: The CDK5-PBK mutual phosphorylation axis serves as a key driver of invasiveness in PitNETs. Proguanil hydrochloride represents a promising candidate dual-target therapeutic agent capable of disrupting this pathway to suppress tumor growth.
Jinghao Jin, Zhaoyi Yi, Hongyun Wang et al.· Genes· 0 citations
p21-activated kinase 4 (PAK4), a Group II PAK family member, is a therapeutically relevant candidate target in cancer, metabolic disease, and tissue injury. However, translation of PAK4 biology into drug candidates has been constrained by the conserved ATP-binding architecture of PAK isoforms, unfavorable pharmacokinetic profiles, and suboptimal clinical efficacy. We summarize the evolution of ATP-competitive Type I inhibitors, Type I½ back-pocket inhibitors, allosteric modulators, and PROTAC degraders, and compare representative compounds using potency, isoform selectivity, cellular activity, oral bioavailability, and development status. Particular emphasis is placed on structural determinants of selectivity, including the αC-helix-dependent hydrophobic back pocket, the inward Asp444/Asp458 floor pocket arrangement, and peripheral microenvironment differences that distinguish PAK4 from Group I PAKs. We also summarize the potential ADMET liabilities-such as pronounced efflux, metabolic instability, and poor oral bioavailability-that may arise from structural modifications aimed at enhancing PAK4 selectivity, and discuss rational optimization strategies to navigate these inherent barriers. Finally, we discuss clinical lessons from PF-3758309 and KPT-9274/padnarsertib and highlight how allosteric inhibitors and PROTAC degraders may help address limitations of conventional ATP-site inhibitors.
Ruiqing Shi, Xue Feng, Zixu Wang et al.· European journal of medicina...· 0 citations
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
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