Discovery of a Small Molecule HPK1 Inhibitor for Immuno-Oncology

HPK1 (hematopoietic progenitor kinase 1, MAP4K1) is a negative regulator of T-cell signaling and has emerged as a promising new target in immuno-oncology. Inhibition of HPK1 is expected to enhance immune system activation and promote T-cell-mediated tumor cell killing. However, achieving sufficient kinase selectivity presents a major challenge, as inhibition of anti-target kinases involved in productive T cell signaling could lead to undesired immunosuppression. In this Flash Talk, Rebecca Gallego, Associate Research Fellow at Pfizer, will present the discovery and optimization of a potent and selective HPK1 inhibitor. She will discuss how mechanistic cellular assays were used to quantify HPK1 inhibition, alongside functional assays and biochemical profiling to evaluate kinase selectivity and avoid key anti-targets. This presentation will highlight how lipophilic efficiency analysis and structure-based drug design guided optimization efforts ultimately led to the discovery of PF-07265028, a potent and selective HPK1 inhibitor which advanced to a Phase 1 clinical trial. 00:00 Welcome and Introduction 07:38 Structure Search 10:31 Presentation 52:04 Q&A If your company doesn’t have a subscription yet, reach out here to inquire about access: https://drughunter.com/plans Recorded on April 16th, 2026, as a Drug Hunter Flash Talk. Sign up to be notified of future sessions here: https://drughunter.com/flash-talk-ser... Sign up for our free newsletter here: https://drughunter.com/newsletter-sig...