Abstract B052: The Kinase Library: A global atlas of the human protein kinome and its applications in drug discovery

Abstract

Mass-spectrometry-based phosphoproteomics now profiles phosphorylation at proteome scale, yet converting site-level measurements into coherent, kinase-centered biology — and into actionable drug discovery decisions — remains a persistent barrier to target nomination, mechanism-of-action confirmation, and resistance management. The Kinase Library addresses this gap with the first-in-class, unbiased, experimentally characterized motif atlas of the human kinome, coupled to enrichment frameworks that translate phosphoproteomics data into quantitative, rank-ordered maps of kinase activity. Rather than relying on heterogeneous annotations or heuristic rules, the Kinase Library grounds inference in experimentally derived kinase-substrate relationships, providing a principled basis for target deconvolution, mechanism-of-action analysis, and comparative pharmacology. The Kinase Library has broad utility across drug discovery and development. It enables on- and off-target mechanism-of-action profiling for small molecules and combinations; delineates adaptive signaling and resistance trajectories that drive clinical relapse; supports time-course and dose-response studies to resolve pathway dynamics and therapeutic windows; nominates rational combination partners by pairing on-target deconvolution with kinome-wide compensatory readouts; and stratifies models and patients in low-N-high-D (few samples with high dimensionality of data) settings where conventional statistics underperform. In preclinical and clinical contexts alike — cell lines, organoids, xenografts, and patient specimens — the Kinase Library delivers harmonized, interpretable kinase signatures that integrate readily with multiomic readouts to generate, prioritize, and de-risk actionable drug-development hypotheses. The novelty of the Kinase Library is twofold. First, scope and provenance: an experimental, unbiased atlas spanning the entire kinome, with comprehensive inclusion of the dark kinome — opening previously inaccessible target space for medicinal chemistry. Second, operationalization: a unified enrichment paradigm that yields robust, rank-ordered kinase programs suitable for go/no-go decision-making — whether the objective is target nomination, combination design, biomarker discovery, patient stratification, or comparative benchmarking across cohorts, modalities, and studies. Looking forward, the Kinase Library is positioned to empower emerging frontiers across the drug-discovery continuum: single-cell and spatial phosphoproteomics; longitudinal "N-of-1" pharmacodynamic monitoring to guide therapy selection; cross-species translation for preclinical model qualification; and cloud-native workflows that interoperate with community pipelines, public datasets, and pharma-internal infrastructure. By elevating kinases from disparate lists of regulated sites to coherent, testable signaling hypotheses, the Kinase Library reframes what phosphoproteomics can deliver — shifting the field from descriptive measurement toward predictive, mechanism-guided drug discovery and intervention. Tomer M. Yaron-Barir, Jared L. Johnson, Lewis C. Cantley. The Kinase Library: A global atlas of the human protein kinome and its applications in drug discovery [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B052.