Targeting RNA-Binding Oncofetal Protein IGF2BP3: Discovery of Potent and Selective Inhibitors

Targeting IGF2BP3 in Cancer: From Molecular Structure and Biology to Early Drug Discovery

RNA-binding proteins (RBPs) remain underexplored as small-molecule targets, although their dysregulation contributes to numerous human diseases, including cancer. RBPs are key regulators of post-transcriptional gene expression, controlling multiple stages of RNA metabolism. Among them, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is an oncofetal RBP that is highly expressed during embryonic development, largely absent in adult tissues, and re-expressed in multiple malignancies. A growing body of evidence supports IGF2BP3 as a diagnostic and prognostic biomarker and a potent oncogenic driver across tumor types, underscoring its potential as a therapeutic target. However, the development of effective IGF2BP3-targeting compounds remains in its early stages. In this review, we first describe the structural organization of IGF2BP3, the molecular basis of RNA recognition, and the mechanisms underlying its dysregulation across human cancers. We then discuss emerging therapeutic approaches, including direct inhibition of IGF2BP3–RNA interactions and indirect strategies that rewire IGF2BP3 expression or activity through epigenetic, epitranscriptomic, and signaling pathways. By critically highlighting the opportunities and limitations of these approaches and their impact on cancer progression, we provide an integrated perspective combining structural biology, medicinal chemistry, and cancer biology to support the development of next-generation IGF2BP3-targeted therapies.

Abbapolin inhibitors of the PLK1 PBD as Prostate Cancer Therapeutics, in vivo activity and synergy with androgen therapy

TARGETED PROTEIN DEGRADATION WITH PROTACS IN CANCER THERAPY: MECHANISMS, CLINICAL ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES

This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.

Abstract B089: Targeting metabolic vulnerabilities in cancer through structure-guided discovery of novel malic enzyme inhibitors

Cancer remains a major global health challenge and urgently requires therapies that improve clinical outcomes and patient quality of life. Tumor cells frequently reprogram metabolism to sustain proliferation and survival, notably by increasing glutamine dependence and upregulating mitochondrial malic enzyme 2 (ME2), which generates pyruvate and NAD(P)H. ME2 is overexpressed in pancreatic, melanoma, and lung cancers, making it a compelling yet underexplored therapeutic target. Recombinant human ME1, ME2, and ME3 were expressed and kinetically characterized in the presence and absence of inhibitors. We solved a complete set of X-ray crystal structures for all three isoforms bound to a potent malic enzyme inhibitor, defining ligand and metal coordination and capturing an unexpected enzyme conformation. These structures guided virtual screening of a curated library of ∼14 million drug-like and fragment molecules to identify novel malic enzyme inhibitors. Biochemical hits were advanced to cellular assays; lead compounds NPD-389 and FLA were evaluated for antiproliferative activity in melanoma and triple-negative breast cancer cell lines. Kinetic analyses revealed distinct activity and inhibition profiles across ME isoforms. X-ray crystallography visualized the isoform-nonselective inhibitor NPD-389 bound in a metal-coordinating mode and stabilizing an unanticipated malic enzyme conformation. Structure-based virtual screening against this conformation yielded multiple novel scaffolds with biochemical inhibitory activity. One scaffold, FLA, displayed a unique selectivity profile and was found bound to ME2 in a previously cryptic pocket that rearranges upon ligand engagement and lies adjacent to the NAD+ cofactor and malate-binding site. In melanoma and triple-negative breast cancer models, both NPD-389 and FLA reduced proliferation, supporting their potential as chemical leads. These findings establish mitochondrial malic enzymes, particularly ME2/ME3, as tractable metabolic targets for cancer therapy. Structural elucidation of NPD-389’s metal-binding mode and FLA’s cryptic/allosteric pocket provides a strong foundation for rational optimization of potency and isoform selectivity. Selective ME inhibitors, either isoform-specific or mitochondrially targeted, represent promising candidates for combination strategies with checkpoint inhibitors or chemotherapy to more effectively disrupt metabolic dependencies in cancer. Ben Krinkel, Yuliana Yosaatmadja, Mark Slayton, Jin Heon Jeon, Jack Flanagan, Sofia Merajver, Christopher Squire, Kerry Loomes. Targeting metabolic vulnerabilities in cancer through structure-guided discovery of novel malic enzyme inhibitors [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 B089.

RNA-Binding Motif Protein 3 as a Therapeutic and Prognostic Target for Drug Discovery

This comprehensive literature review delves into the multifaceted roles of RNA-binding motif protein 3 (RBM3) in cellular processes, disease pathogenesis, and therapeutic potential. RBM3 has been implicated in shaping cell morphology, synaptic protection in neurodegenerative conditions, and regulating gene expression through binding to specific RNA sequences. In cancer, RBM3 exhibits contrasting effects, influencing cell proliferation, tumorigenic potential, and RNA splicing. Clinical studies suggest RBM3 as a predictive biomarker in chemotherapy response for muscle-invasive bladder cancer. Despite promising therapeutic implications in neuroprotection and cancer, challenges persist in understanding the regulatory mechanisms and clinical behavior of RBM3. Further research is warranted to elucidate the molecular mechanisms underlying RBM3’s diverse functions and its significance as a potential target for personalized medicine in cancer therapy. This review underscores the pivotal role of RBPs, particularly RBM3, in disease progression and highlights the need for continued investigation to harness their therapeutic potential effectively. This review evaluates evidence available through December 2025, with particular emphasis on studies published between 2010 and 2025.

A novel peptide encoded by circTLL1 drives osimertinib resistance in lung cancer by modulating the NT5C2/Ras/PI3K axis.

BACKGROUND Acquired resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). Although circular RNAs (circRNAs) have been increasingly implicated in drug resistance, most studies have focused on their canonical role as microRNA sponges, while their capacity to encode functional micropeptides remains largely unexplored. This study aimed to identify novel circRNAs involved in osimertinib resistance and to characterize their regulatory functions at the protein level. METHODS Osimertinib-resistant (OR) NSCLC cell lines were established and validated. High-throughput RNA sequencing was performed to compare the circRNA expression profiles between parental and OR cells. The function of the candidate circRNA was assessed through a series of in vitro and in vivo experiments, including cell viability assays, apoptosis analysis, and xenograft mouse models. Mechanistic investigations involved mass spectrometry, co-immunoprecipitation and western blotting to explore its protein-coding potential and downstream signaling pathways. RESULTS We identified a novel circRNA, termed circTLL1, that was stably and significantly upregulated in OR-NSCLC cells. Functionally, overexpression of circTLL1 promoted osimertinib resistance, whereas its knockdown restored drug sensitivity both in vitro and in vivo. Mechanistically, we discovered that circTLL1 harbors an open reading frame (ORF) that is translated into a novel 90-amino-acid protein, which we designated circTLL1-90aa. Further investigation revealed that circTLL1-90aa directly interacts with and promotes the degradation of 5'-nucleotidase, cytosolic II (NT5C2), thereby uncoupling nucleotide metabolism from its normal regulatory constraints. The consequent downregulation of NT5C2 leads to elevated GTP levels and leading to the sustained activation of the downstream Ras/PI3K/AKT signaling pathway. CONCLUSION Our findings unveil a previously unrecognized circRNA/micropeptide/metabolism cascade underlying osimertinib resistance. The identification of the circTLL1-90aa/NT5C2/Ras/PI3K axis not only expands the functional repertoire of the non-coding genome but also provides new insights into the complexity of drug resistance. Given its selective upregulation in resistant cells, circTLL1-90aa holds promise both as a predictive biomarker for treatment stratification and as an actionable therapeutic target, offering a novel strategy to overcome osimertinib resistance in NSCLC patients.