Download

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.

Download

In drug discovery, proactive toxicological risk assessment of candidate compounds is crucial for avoiding clinical-stage failure and post-market withdrawal. However, traditional preclinical safety evaluation strategies have significant limitations: in vivo animal studies exhibit low human relevance (translatability) due to significant species differences and face dual pressures of ethics and cost; while conventional in vitro binding assays are inadequate for predicting functional biological effects. Notably, approximately 75% of clinical adverse drug reactions (ADRs) originate from dose-dependent off-target effects, highlighting an urgent need for more accurate early-risk identification tools. To address these challenges, the IQ DruSafe consortium— a preeminent alliance of global pharmaceutical companies—has championed the enhancement of preclinical predictive power through the expansion and refinement of secondary pharmacology screening strategies. This study is aligned with this initiative and aims to investigate the implementation of an advanced in vitro secondary pharmacology screening system utilizing functional assay formats. By generating richer pharmacological information beyond mere binding affinity, this strategy seeks to enable a more accurate and earlier identification of potential safety liabilities, thereby providing highly translatable safety insights for the optimization of lead compounds.

Download

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.

Download

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.