Abstract C049: IMTAC™: A proteome-wide live-cell screening platform for discovering covalent binders to diverse targets including GPCRs, phosphatases, and more

Abstract Hit generation remains a critical bottleneck in drug discovery, particularly for novel or "undruggable" targets, due to limited assay availability, off-target artifacts in live-cell screening, poor physiological relevance of purified protein assays and constrained chemical diversity of traditional libraries. BridGene’s proprietary IMTAC™ (Isobaric Mass Tagged Affinity Characterization) platform addresses these hurdles by integrating a highly diverse covalent small molecule library with advanced live-cell chemical proteomics and quantitative mass spectrometry. This innovative approach enables direct, on-target binding detection at endogenous protein levels, providing a universal and unbiased readout to identify antagonists, agonists, allosteric modulators, and silent binders. It also minimizes false positives, delivers proteome-wide selectivity profiles, and reveals transient, novel binding pockets under native cellular environments. We showcase IMTAC™-enabled hit discovery across diverse target classes to highlight the platform’s broad capability and translational potential: GPCRs: • 5-HT2A: BGP-1951 inhibited serotonin-induced calcium influx and exhibited a clear off-targets (proteome-wide selectivity) profile, representing a novel strategy to avoid toxicity seen with traditional central nervous system (CNS)-targeted 5-HT2A antagonists. • CXCR4: BGP-2992 identified as a positive allosteric modulator (PAM), enhancing SDF-1α–regulated cAMP reduction, with therapeutic potential in neuroinflammation and regeneration. Phosphatases: • ENPP1: BGP-15341 inhibited ENPP1 enzymatic activity with a nM IC50, providing a compelling starting point for further optimization in immune-oncology applications. • PTPN2: BGP-1900 is as a silent binder that targets a unique cysteine residue of PTPN2, offering a novel strategy to enable selective degradation of PTPN2 via PROTAC approaches. Kinases: • CDK7: A promising oncology target where selectivity is crucial to avoid pan-CDK inhibition associated toxicity. We identified BGP-21172 as a CDK7-selective binder with low nM IC50, and minimal CDK4/9 activity in biochemical kinase assays. • ADK: ADK inhibition augments adenosine availability, which has been shown anti-seizure, anti-inflammatory properties in animal models. We identified BGP-1892 and BGP-13486 as potent ADK binders in NanoBRET target engagement assay. By combining covalent chemistry, live-cell proteomics, and unbiased engagement profiling, the IMTAC™ platform enables the identification of covalent binders across a broad spectrum of targets—including those traditionally considered "hard to drug." This approach significantly expands the druggable proteome and facilitates the discovery of high-quality chemical matter for historically inaccessible targets. BridGene is actively advancing these compounds through medicinal chemistry efforts to improve potency, selectivity, and drug-like properties with the goal of developing first- or best-in-class therapeutics. Citation Format: Vivian Zhang, Yining Hao, Iris Dong, Shanshan Deng, Logan Schachtner, Ning Deng, Hiroko Tanaka, Anna Chen, Ping Cao, Shirley Guo. IMTAC™: A proteome-wide live-cell screening platform for discovering covalent binders to diverse targets including GPCRs, phosphatases, and more [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C049.