Abstract 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. Citation Format: Allan Michael Jordan, Daniel Clare, Kam Chohan, Rick Davies, Jonathan Finlayson, Euan Fordyce, Clare Hammond, Philip MacFaul, Christopher Pearce, Raquel Faba Rodriguez, Alexandra Stowell, Denise Swift, Megan Thompson, Graeme Walker, Terence Wu. DiscoveryDirect: Extending direct-to-biology paradigms to accelerate oncology drug discovery abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6428.
Jordan et al. (Fri,) studied this question.