ICE Bioscience Posters

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Breast cancer remains a leading cause of cancer-related mortality worldwide. While the simultaneous inhibition of PI3Kα and CDK4/6 has recently been clinically validated for advanced breast cancer, combination regimens of distinct targeted agents are often limited by overlapping toxicities and complex pharmacokinetics. To address these clinical hurdles and overcome therapeutic resistance, we developed a novel series of single-molecule dual PI3K/CDK4- 6 inhibitors by structure-based drug design strategy. Through extensive SAR studies, lead compounds 11 and 13 were identified, exhibiting nanomolar potency against PI3Kα and CDK4/6, high kinase selectivity, and potent antiproliferative activity in breast cancer cell lines. Compound 13 demonstrated robust in vivo efficacy in a T47D xenograft model, comparable to the Palbociclib–BKM120 combination with a good safety profile. This work highlights single- molecule dual PI3K/CDK4-6 inhibition as a highly promising therapeutic strategy for breast cancer.

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We present an integrated hit discovery platform for B7‑H3 macrocyclic peptide binder screening that synergizes high‑throughput biophysical screening (SPR, SPS) with phage display technology. State-of-the-art protein structure prediction methods were employed to model the peptide–receptor complex, combined with binding free-energy calculations, thereby enabling the rapid identification and optimization of high-affinity cyclic peptide binders against oncology targets.

Our methodology employs parallel in vitro biophysical assays and phage display library screening. Protein structure prediction tools were also utilized to model the cyclic peptide–receptor complex structure, followed by binding free-energy calculations. The sequences obtained from phage display library screening were ranked and selected based on the Ipae metric and binding free-energy values. Target validation was achieved through engineered recombinant protein constructs (including B7-H3, FAP, EGFR, B7-H4 and GPC3) and isogenic cell lines with uniform target expression. Comprehensive evaluation was performed using modular functional assays measuring binding affinity and cellular internalization kinetics.

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Antibody-drug conjugates (ADCs) represent a promising antineoplastic strategy by combining antibody targeting with potent cytotoxic drugs. However, clinical challenges remain, including tumor non-responsiveness, drug resistance, and disease relapse, largely due to tumor heterogeneity and resistance mechanisms. Dual-payload ADCs have emerged as an innovative approach to improve efficacy through synergistic cytotoxicity, overcome resistance, and support flexible dosing regimens. The development of such ADCs relies on identifying effective payload combinations, which can be efficiently explored using cell panel screening and drug-resistant cell models. In this study, we performed large-scale combination screening in ADC-resistant cell lines to identify synergistic payload pairs. The screening panel included more than 120 targeted agents and chemotherapeutics. Our results identified that ATR inhibitors as well as CHK1/2 inhibitors exhibited favorable synergistic effects in combination with Topoisomerase I (TOPO1) inhibitors, whose detailed mechanisms warrant further validation. This optimized combination serves as a direct candidate for dual-payload ADC development, with the potential to accelerate the discovery and translation of next-generation ADC therapies.

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KRAS mutations are dominant oncogenic drivers in many solid tumors. Although KRAS G12C inhibitors and pan-RAS targeted agents have shown clinical promise, intrinsic and acquired resistance remains a major challenge.In this study, we established a well-validated panel of resistant cell lines against KRAS G12C inhibitors, pan-RAS molecular glues, and pan-RAS inhibitors. We performed multi-omics characterization, cross-resistance profiling, and genomic analysis to define key resistance features, including copy number alterations and secondary KRAS mutations. This platform provides a robust preclinical model for investigating resistance mechanisms and supporting the development of next-generation RAS-targeted therapies.