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Dual-payload antibody-drug conjugates (ADCs) represent a next-generation therapeutic strategy designed to overcome tumor heterogeneity and drug resistance by delivering two distinct payloads with synergistic potential. This study aimed to identify an optimal dual-payload combination to address the challenge of therapeutic resistance in colorectal cancer (CRC), focusing on inhibitors of DNA damage response (DDR) pathways.

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In drug discovery, proactive toxicological risk assessment is critical for mitigating clinical-stage attrition and post-market withdrawals. Traditional preclinical strategies face significant limitations: in vivo models often exhibit poor human translatability due to species differences, alongside ethical and cost constraints, while conventional in vitro binding assays fail to capture functional biological effects. Given that approximately 75% of clinical adverse drug reactions (ADRs) are dose-dependent and originate from off-target interactions, the demand for more predictive early-risk identification tools is pressing. Addressing this need, the IQ DruSafe consortium—a preeminent alliance of global pharmaceutical companies—has advocated for enhancing predictive power by expanding and refining secondary pharmacology screening. Aligned with this initiative and the SLAS Europe 2026 theme of “Shaping the Future of Life Sciences and Automation,” this study investigates the implementation of an advanced, automation-driven in vitro screening system utilizing functional assay formats. By integrating high-throughput automation platforms, such as automated liquid handling systems, this strategy moves beyond mere binding affinity to generate rich, quantitative pharmacological data with high precision and reproducibility. The purpose is to leverage this automated, functionally-oriented screening to enable a more accurate and earlier identification of potential safety liabilities, thereby providing highly translatable insights for lead compound optimization and reshaping the paradigm of early safety assessment.

The ICESTP SAFETYPANEL™ 77 Dose Response platform provides a comprehensive functional screening strategy that integrates single-point primary screening with quantitative dose-response (curve-based) profiling. This strategy is supported by a broad suite of mechanism-relevant functional assay technologies, including FLIPR calcium flux assay, HTRF, ADP-Glo, fluorescence polarization (FP), and other mechanism-relevant functional formats. The entire workflow exemplifies the convergence of functional biology and advanced automation. The process is fully automated—from initial compound handling via Echo and Firefly systems, through functional readouts on platforms like BMG. This integrated approach ensures exceptional efficiency, reproducibility, and data richness. By accelerating the safety profiling process, minimizing manual error, and delivering mechanistically insightful, quantitative datasets (e.g., IC₅₀/EC₅₀), the platform enables more reliable optimization of candidate compounds early in the drug discovery pipeline.

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The DNA Damage Response (DDR) pathway is the core biological system through which cells detect and repair genomic lesions. Targeting DDR pathways and inhibiting DNA repair mechanisms has emerged as a highly promising strategy in cancer therapy, with significant breakthroughs achieved in the development of DDR inhibitors. Antibody-drug conjugates (ADCs)—which combine the precise targeting of antibodies with the potent cytotoxicity of drugs—represent a promising antineoplastic therapy. However, current ADCs face critical challenges, including non-responsive cancers, drug resistance, and rapid patient relapse, primarily driven by tumor heterogeneity and resistance. To address these issues, dual-payload ADCs have emerged as an innovative strategy: they deliver two cytotoxic agents to enhance efficacy via synergistic effects, mitigate resistance, and enable flexible dosing. Despite their potential, dual-payload ADC development remains complex; cell panel-based studies and drug-resistant cell lines serve as powerful tools to explore effective dual-payload ADCs by evaluating drug combination synergies and elucidating resistance mechanisms. To advance the development of DDR pathway-based dual-payload ADCs, this study leveraged an in-house DDR platform to conduct large-scale synergy screening in ADC-resistant cell lines. The screening panel included over 120 targeted molecules and chemotherapeutics, covering DDR core pathway proteins (e.g., WRN, PARP, ATR, DNAPK), cell cycle regulators, and kinase families such as tyrosine kinases. Screening results revealed that ATR inhibitors combined with Topoisomerase I (TOPO1) inhibitors exhibit strong synergistic activity; their specific molecular mechanisms require further validation. This optimal combination provides a direct candidate for DDR pathway-targeted dual-payload ADC development, with the potential to accelerate the research, development, and translation of next-generation DDR-enabled ADC modalities.

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Signal Transducer and Activator of Transcription 6 (STAT6) is a central mediator of IL‑4/IL‑13 signaling, and its dysregulation contributes to asthma, atopic dermatitis, fibrosis, and other immune‑driven diseases. With STAT6 therapeutics such as KT‑621 and REX‑8756 advancing clinically, there is growing demand for platforms that generate precise, translationally relevant data.

ICE Biosciences has developed a comprehensive, end‑to‑end workflow for STAT6 inhibitor and PROTAC discovery, built on our integrated target- ed protein degradation (TPD) platform and fully compatible with high‑throughput screening (HTS). Orthogonal biochemical and biophysical assays, including dual‑injection SPR for binding‑site resolution, establish robust target engagement. Cellular assays extend this to degradation, employing WB, FACS, and HiBiT readouts. To enhance translational relevance, functional assays using human primary samples, such as cytokine measurements in blood and smooth muscle cells, are developed. Selectivity and cross‑species profiling ensure confidence across models, while in‑depth MoA studies provide mechanistic clarity. Beyond molecular and cellular characterization, the workflow integrates comprehensive safety evaluation with advancing in  studies. By uniting biochemical precision, cellular function, and pharmacological depth, this platform delivers actionable insights to accelerate next‑generation STAT6 therapeutics for autoimmune and inflammatory diseases.