ICE Bioscience Posters

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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. Here, we established a well-validated panel of resistant cell lines against KRAS G12C/G12D 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. We further evaluated diverse combination strategies to overcome RAS-driven resistance in this platform. This model provides a robust preclinical system for investigating resistance mechanisms and supporting next-generation RAS-targeted therapy development.

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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) are key targeted therapies, yet drug resistance remains a major clinical challenge. To address this, we established a panel of 28 well-characterized ADC-resistant cell lines, validated via resistance profiling, RNA-seq, and WES analysis. This platform enables high-throughput screening of novel payloads and combinations to overcome resistance.

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RIPTAC (Regulated Induced Proximity Targeting Chimeras) introduces a novel strategy that leverages induced proximity to achieve selective cancer cell killing. Using AR–BRD4 RIPTAC II-5 as a tool compound, we integrated biochemical screening, computational docking, and multi-level cellular and in vivo assays to establish a direct link between target engagement and therapeutic efficacy. Biochemical evaluation confirmed binary and ternary affinity, supported by computational simulations that predicted novel AR–BRD4 ternary protein–protein interactions (neoPPIs) consistent with cooperativity observed experimentally. II-5’s distinct slow on/off binding kinetics stabilize ternary complexes, translating into superior activity in ternary formation and downstream signaling modulation. Cellular assays demonstrated that II-5 induces ternary complexes in HEK293T AR OE, VCaP, and LNCaP cells, correlating with strong inhibition of BRD4-driven signaling (c-Myc) while only moderately inhibit AR signaling (reporter and PSA). In vivo CDX models further validated ternary complex formation, PSA reduction, and pharmacodynamic biomarker responses, showing that ternary assembly is preserved across biochemical, cellular, and tumor tissue contexts. II-5 was highly potent in AR-high prostate cancer models, with efficacy scaling across AR mutants and expression levels, highlighting a mechanistic correlation between AR expression and therapeutic effect. This enables RIPTAC to address resistance mechanisms such as AR amplification, point mutations, etc. Safety panel profiling indicates an overall favorable profile with limited off-target activity. Beyond AR–BRD4, RIPTAC expands the induced proximity landscape, aligning with TCIP paradigms and demonstrating broader applicability across oncogenic drivers. Together, computational and experimental evidence converge to highlight ternary complex stability and AR expression dependence as the mechanistic drivers of RIPTAC’s therapeutic window. Importantly, our induced proximity platform, built on extensive expertise in targeted protein degradation (TPD), can be rapidly migrated to other target pairs, enabling first-in-class drug discovery programs and supporting both domestic and international partners.