DiscoveryDirect：拓展直达生物学范式以加速肿瘤学药物发现

The average timeline from project initiation to preclinical candidate delivery in oncology drug discovery is approximately four years. To compress these timelines, direct-to-biology strategies are increasingly employed to expedite early decision-making and compound progression. However, conventional approaches often remain limited to biophysical off-rate assessments of crude reaction mixtures (CRMs), restricting their utility. To overcome these constraints, we have expanded this paradigm through integrated methodologies, including Direct-to-Crystallography (D2C), to validate hits and elucidate structure-activity relationships (SAR), enabling pre-candidate delivery in as little as 18 months. Harnessing our Hit Synergy platform which combines complementary screening technologies, we rapidly generated novel, high quality and structurally diverse hits for a challenging and clinically relevant oncology target. Early deployment of D2C, using existing HTS liquid stocks, delivered ligand-bound structures without delays associated with hit re-synthesis or re-acquisition. These structures confirmed target engagement and revealed novel binding interactions. Orthogonal hit validation employed direct-to-biology approaches such as off-rate screening, alongside tailored biochemical and cellular assays on purified samples. Integration of structural insights and biological data accelerated hit expansion via high-throughput chemistry (HTC) and complementary direct-to-biology assays validated for both pure compounds and CRMs. Robust D2C determinations from CRMs yielding as little as 15% product further streamlined SAR generation and hypothesis testing, influencing medicinal chemistry design and decision making and compressing the design-make-test cycle. Generative AI-driven idea generation and direct-to-physicochemical assays further supported optimization for developability. Together, this fully integrated, multi-modal workflow enabled rapid, holistic decision-making at critical project stages, delivering pre-candidate quality derivatives in a significantly truncated timeframe. By embedding direct-to-discovery methodologies throughout the pipeline, we successfully accelerated progression from hit identification to candidate selection, advancing novel therapeutics toward the clinic with unprecedented efficiency.